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Neural Stem Cells and Nutrients: Poised Between Quiescence and Exhaustion
Abstract
Adult neurogenesis initiated by neural stem cells (NSCs) contributes to brain homeostasis, damage repair, and cognition. Energy metabolism plays a pivotal role in neurogenic cell fate decisions regarding self-renewal, expansion and multilineage differentiation. NSCs need to fine-tune quiescence and proliferation/commitment to guarantee lifelong neurogenesis and avoid premature exhaustion. Accumulating evidence supports a model whereby calorie restriction or increased energy expenditure reinforce NSC quiescence and promote self-renewal. Conversely, growth/proliferation inputs and anabolic signals, although necessary for neurogenesis, deplete the NSCs pool in the long run. This framework incorporates the emerging neurogenic roles of nutrient-sensing signaling pathways, providing a rationale for the alarming connection between nutritional imbalances, metabolic disorders and accelerated brain aging.
... Neurogenesis is described as the maturation of committed cells from NSCs (Cavallucci et al. 2016). Neurogenesis takes place throughout life, giving rise to new cells within the niche and substitute for the cell loss within the adult CNS. ...
... Within the NSC niche, neurotransmitter, cytokine, and factor trafficking have significant roles in behavior and fate of NSCs (Andreotti et al. 2019). NSCs of different morphologies that respond to differential external stimuli are thought to coexist within the niche (Bao and Song 2018), where the fate of NSCs is delicately regulated by the discriminating microenvironment including cytokines, hormones, and growth factors and also extrinsically, stress and aging (Cavallucci et al. 2016). ...
... Neurogenesis, that is differentiation of committed cells from NSCs, and self-renewal of NSCs are regulated by immediate microenvironment (Andreotti et al. 2019). Both in developing CNS and throughout the adult life, the differentiation and proliferation of NSCs are strictly modulated by intrinsic and extrinsic factors, i.e., cytokines, hormones, and growth factors, as well as aging, stress, and exercise (Cavallucci et al. 2016). Given that numerous cellular pathways are involved in these procedures, it is obvious that there is a great number of cellular interactions, cross-interactions of pathways, and molecular cascades. ...
The development of the CNS is a complex and well-regulated process, where stem cells differentiate into committed cells depending on the stimuli from the microenvironment. Alterations of oxygen levels were stated to be significant in terms of brain development and neurogenesis during embryonic development, as well as the adult neurogenesis. As a product of oxygen processing, hydrogen peroxide (H2O2) has been established as a key regulator, acting as a secondary messenger, of signal transduction and cellular biological functions. H2O2 is involved in survival, proliferation, and differentiation of neural stem cells into committed cells of the CNS. Effects of different concentrations of exogenous H2O2 on neuronal differentiation and the molecular pathways involved are yet to be clearly understood. Here, we investigated the concentration-dependent effects of H2O2 on differentiation of neural stem cells using CGR8 embryonic mouse stem cell line. We have demonstrated that treated doses of H2O2 suppress neural differentiation; additionally, our study suggests that relatively high doses of exogenous H2O2 suppress the differentiation process of neural stem cells through AKT and p38 pathways.
... In addition to activated microglia, nutrient-sensing signaling and energy metabolism play a critical role in maintaining the balance between quiescence and activation of stem cells. Under normal low-oxygen conditions, qNSCs predominantly utilize glycolytic metabolism rather than mitochondrial oxidative phosphorylation (Cavallucci et al., 2016;Yu et al., 2024). Thus, this is due to hyperexpression of the hypoxia-inducible factors (HIFs, particularly HIF-1) that are activated under oxygen-deprived state and contribute the stem cell pool maintenance and their resting state (Cavallucci et al., 2016). ...
... Under normal low-oxygen conditions, qNSCs predominantly utilize glycolytic metabolism rather than mitochondrial oxidative phosphorylation (Cavallucci et al., 2016;Yu et al., 2024). Thus, this is due to hyperexpression of the hypoxia-inducible factors (HIFs, particularly HIF-1) that are activated under oxygen-deprived state and contribute the stem cell pool maintenance and their resting state (Cavallucci et al., 2016). Accordingly, the metabolic changes (such as destruction of HIFs in excess of oxygen) may promote the switch of NCSs from state of rest to an active one (Urbán and Cheung, 2021). ...
The global extension of human lifespan has intensified the focus on aging, yet its underlying mechanisms remain inadequately understood. The article highlights aspects of genetic susceptibility to impaired brain bioenergetics, trends in age-related gene expression related to neuroinflammation and brain senescence, and the impact of stem cell exhaustion and quiescence on accelerated brain aging. We also review the accumulation of senescent cells, mitochondrial dysfunction, and metabolic disturbances as central pathological processes in aging, emphasizing how these factors contribute to inflammation and disrupt cellular competition defining the aging trajectory. Furthermore, we discuss emerging therapeutic strategies and the future potential of integrating advanced technologies to refine aging assessments. The combination of several methods including genetic analysis, neuroimaging techniques, cognitive tests and digital twins, offer a novel approach by simulating and monitoring individual health and aging trajectories, thereby providing more accurate and personalized insights. Conclusively, the accurate estimation of brain aging trajectories is crucial for understanding and managing aging processes, potentially transforming preventive and therapeutic strategies to improve health outcomes in aging populations.
... Furthermore, aberrant adult neurogenesis has been reported in mice models for nutrient-triggered signals impairment, thus confirming that nutrient-regulated switches influence NSCs fate decisions. The transition between quiescent and activated states is a critical step, as the required cell cycle entry is a major energetic commitment (Cavallucci et al., 2016;Wentling et al., 2019). For this reason, nutrient-responsive pathways and transducers, such as the growth differentiation factor-11 (GDF11), the insulin-IGF cascade, the AMPK/mTOR axis, and the transcription regulators CREB and SIRT1 have been included, alongside the canonical "developmental" signals (e.g., Notch and Wnt), in the molecular networks controlling NSCs self-renewal, migration, and differentiation, in response to local and systemic inputs (Figure 1). ...
... Nevertheless, the molecular pathways underlying metabolic regulation of neurogenesis, are still poorly understood. Their full comprehension, as well as their interplay with novel dietary and/or pharmacological approaches, aiming at improving neurogenic activity and delaying its age-related decline, may be of help in the prevention of neurodegenerative disorders and brain aging (Cavallucci et al., 2016). Nutrient pathways control of NSCs fate. ...
Since the discovery of Neural Stem Cells (NSCs) there are still mechanism to be clarified, such as the role of mitochondrial metabolism in the regulation of endogenous adult neurogenesis and its implication in neurodegeneration. Although stem cells require glycolysis to maintain their stemness, they can perform oxidative phosphorylation and it is becoming more and more evident that mitochondria are central players, not only for ATP production but also for neuronal differentiation’s steps regulation, through their ability to handle cellular redox state, intracellular signaling, epigenetic state of the cell, as well as the gut microbiota-brain axis, upon dietary influences. In this scenario, the 8-oxoguanine DNA glycosylase (OGG1) repair system would link mitochondrial DNA integrity to the modulation of neural differentiation. On the other side, there is an increasing interest in NSCs generation, from induced pluripotent stem cells, as a clinical model for neurodegenerative diseases (NDs), although this methodology still presents several drawbacks, mainly related to the reprogramming process. Indeed, high levels of reactive oxygen species (ROS), associated with telomere shortening, genomic instability, and defective mitochondrial dynamics, lead to pluripotency limitation and reprogramming efficiency’s reduction. Moreover, while a physiological or moderate ROS increase serves as a signaling mechanism, to activate differentiation and suppress self-renewal, excessive oxidative stress is a common feature of NDs and aging. This ROS-dependent regulatory effect might be modulated by newly identified ROS suppressors, including the NAD⁺-dependent deacetylase enzymes family called Sirtuins (SIRTs). Recently, the importance of subcellular localization of NAD synthesis has been coupled to different roles for NAD in chromatin stability, DNA repair, circadian rhythms, and longevity. SIRTs have been described as involved in the control of both telomere’s chromatin state and expression of nuclear gene involved in the regulation of mitochondrial gene expression, as well as in several NDs and aging. SIRTs are ubiquitously expressed in the mammalian brain, where they play important roles. In this review we summarize the current knowledge on how SIRTs-dependent modulation of mitochondrial metabolism could impact on neurogenesis and neurodegeneration, focusing mainly on ROS function and their role in SIRTs-mediated cell reprogramming and telomere protection.
... Two generally accepted canonical domains in the adult central nervous system that keep a reservoir of NSCs are the subventricular zone near the lateral ventricles and the subgranular zone of the dentate gyrus, where most of the NSCs remains quiescent (Cheung and Rando, 2013;Urban et al., 2019;Kobayashi and Kageyama, 2021). The quiescent state of NSCs, which is characterized by low metabolic rate and low protein and RNA synthesis, is vital to the preservation of their genomic integrity and essential functional properties (Cavallucci et al., 2016). Quiescent NSCs (qNSCs) rest at the G0 phase of the cell cycle and do not express proliferation markers, such as Ki-67 and MCM2 (Codega et al., 2014). ...
... NSCs maintain a delicate balance with proliferating and quiescence. This equilibrium is essential for NSC homeostasis, and its disruption may lead to brain aging and its associated diseases (Cavallucci et al., 2016). Discrete NSC niche stimuli play indispensable roles in determining whether NSCs remain quiescent or reenter the cell cycle (Fuentealba et al., 2012;Kjell et al., 2020). ...
Neural stem cell (NSC) quiescence plays pivotal roles in avoiding exhaustion of NSCs and securing sustainable neurogenesis in the adult brain. The maintenance of quiescence and transition between proliferation and quiescence are complex processes associated with multiple niche signals and environmental stimuli. Exosomes are small extracellular vesicles (sEVs) containing functional cargos such as proteins, microRNAs, and mRNAs. The role of sEVs in NSC quiescence has not been fully investigated. Here, we applied proteomics to analyze the protein cargos of sEVs derived from proliferating, quiescent, and reactivating NSCs. Our findings revealed fluctuation of expression levels and functional clusters of gene ontology annotations of differentially expressed proteins especially in protein translation and vesicular transport among three sources of exosomes. Moreover, the use of exosome inhibitors revealed exosome contribution to entrance into as well as maintenance of quiescence. Exosome inhibition delayed entrance into quiescence, induced quiescent NSCs to exit from the G0 phase of the cell cycle, and significantly upregulated protein translation in quiescent NSCs. Our results suggest that NSC exosomes are involved in attenuating protein synthesis and thereby regulating the quiescence of NSCs.
... This is interesting since higher oxygen level would help maintain NSC, as well as GSC which have reached the SVZ, in a quiescent and undifferentiated states (104). NSCs in the SVZ are in close contact with the BBB which constantly expose them to circulating molecules and nutrients (105). As already mentioned above, the BBB is often altered in GBM brains (92), which could lead to blood vessel leakage and nutrients unbalance in the SVZ and consequently influence GSC quiescence state (105). ...
... NSCs in the SVZ are in close contact with the BBB which constantly expose them to circulating molecules and nutrients (105). As already mentioned above, the BBB is often altered in GBM brains (92), which could lead to blood vessel leakage and nutrients unbalance in the SVZ and consequently influence GSC quiescence state (105). ...
Both in adult and children, high-grade gliomas (WHO grades III and IV) account for a high proportion of death due to cancer. This poor prognosis is a direct consequence of tumor recurrences occurring within few months despite a multimodal therapy consisting of a surgical resection followed by chemotherapy and radiotherapy. There is increasing evidence that glioma stem cells (GSCs) contribute to tumor recurrences. In fact, GSCs can migrate out of the tumor mass and reach the subventricular zone (SVZ), a neurogenic niche persisting after birth. Once nested in the SVZ, GSCs can escape a surgical intervention and resist to treatments. The present review will define GSCs and describe their similarities with neural stem cells, residents of the SVZ. The architectural organization of the SVZ will be described both for humans and rodents. The migratory routes taken by GSCs to reach the SVZ and the signaling pathways involved in their migration will also be described hereafter. In addition, we will debate the advantages of the microenvironment provided by the SVZ for GSCs and how this could contribute to tumor recurrences. Finally, we will discuss the clinical relevance of the SVZ in adult GBM and pediatric HGG and the therapeutic advantages of targeting that neurogenic region in both clinical situations.
... The cell cycle state is a determining factor for the metabolic status of stem cells. Once animals enter adulthood, stem cells in many tissues, such as the hematopoietic stem cells (HSCs) and neural stem cells (NSCs), mostly remain quiescent and only enter the cell cycle and proliferate periodically to selfrenew and replenish the tissue [15][16][17][18][19]. Quiescent stem cells have low mitochondrial activity and primarily rely on glycolysis for energy production [20][21][22]. ...
... Compared to mitochondrial oxidative phosphorylation (OXPHOS), glycolysis leads to less ATP production, but is sufficient to sustain the low energy demand of quiescent stem cells. Reliance on glycolysis bypasses mitochondrial OXPHOS and protects stem cells from reactive oxygen species (ROS), and ensure long-term stem cell maintenance, as elevated levels of ROS lead to loss of stem cell quiescence, differentiation, and apoptosis [11,19,[23][24][25][26][27][28][29]. ...
Purpose of Review
Diet has profound impacts on health and longevity. Evidence is emerging to suggest that diet impinges upon the metabolic pathways in tissue-specific stem cells to influence health and disease. Here, we review the similarities and differences in the metabolism of stem cells from several tissues and highlight the mitochondrial metabolic checkpoint in stem cell maintenance and aging. We discuss how diet engages the nutrient sensing metabolic pathways and impacts stem cell maintenance. Finally, we explore the therapeutic implications of dietary and metabolic regulation of stem cells.
Recent Findings
Stem cell transition from quiescence to proliferation is associated with a metabolic switch from glycolysis to mitochondrial OXPHOS and the mitochondrial metabolic checkpoint is critically controlled by the nutrient sensors SIRT2, SIRT3, and SIRT7 in hematopoietic stem cells. Intestine stem cell homeostasis during aging and in response to diet is critically dependent on fatty acid metabolism and ketone bodies and is influenced by the niche mediated by the nutrient sensor mTOR.
Summary
Nutrient sensing metabolic pathways critically regulate stem cell maintenance during aging and in response to diet. Elucidating the molecular mechanisms underlying dietary and metabolic regulation of stem cells provides novel insights for stem cell biology and may be targeted therapeutically to reverse stem cell aging and tissue degeneration.
... While most of these regulatory molecules have been studied in relation to classic neurogenic zones, they likely play similar roles in the hypothalamic neurogenic process as well [89][90][91]. There are excellent reviews on these regulatory molecules and pathways [15,47,92,93]. Here we describe some of the more extensively studied regulatory molecules and pathways. ...
... Most adult NSCs are quiescent. The balance between their quiescent and proliferative states is tightly regulated [93][94][95]. Dysregulation and/or loss of quiescence may result in a premature proliferation of NSCs ultimately leading to the depletion of neural stem and progenitor cells [96][97][98][99][100]. Stem cells undergo both symmetric and asymmetric divisions. ...
In the mammalian brain, adult neurogenesis has been extensively studied in the hippocampal sub-granular zone and the sub-ventricular zone of the anterolateral ventricles. However, growing evidence suggests that new cells are not only “born” constitutively in the adult hypothalamus, but many of these cells also differentiate into neurons and glia and serve specific functions. The preoptic-hypothalamic area plays a central role in the regulation of many critical functions, including sleep–wakefulness and circadian rhythms. While a role for adult hippocampal neurogenesis in regulating hippocampus-dependent functions, including cognition, has been extensively studied, adult hypothalamic neurogenic process and its contributions to various hypothalamic functions, including sleep–wake regulation are just beginning to unravel. This review is aimed at providing the current understanding of the hypothalamic adult neurogenic processes and the extent to which it affects hypothalamic functions, including sleep–wake regulation. We propose that hypothalamic neurogenic processes are vital for maintaining the proper functioning of the hypothalamic sleep–wake and circadian systems in the face of regulatory challenges. Sleep–wake disturbance is a frequent and challenging problem of aging and age-related neurodegenerative diseases. Aging is also associated with a decline in the neurogenic process. We discuss a hypothesis that a decrease in the hypothalamic neurogenic process underlies the aging of its sleep–wake and circadian systems and associated sleep–wake disturbance. We further discuss whether neuro-regenerative approaches, including pharmacological and non-pharmacological stimulation of endogenous neural stem and progenitor cells in hypothalamic neurogenic niches, can be used for mitigating sleep–wake and other hypothalamic dysfunctions in aging.
... In rodents, adult neurogenesis persists in the subgranular zone (SGZ) of the hippocampus, the ventricular and subventricular zone (SVZ) of the lateral ventricle, and along the third ventricle and the mediobasal hypothalamus (MBH) [34,35]. Although the production of new neurons diminishes dramatically with age, newly generated neurons are involved in maintaining brain functions. ...
... Therefore, we can surmise that CR maintains adult neurogenesis in an appropriate state later in life. Indeed, accumulating evidence supports this hypothesis [34]. In particular, aging-related atrophy of the gray matter in subcortical regions of the brain in rhesus monkeys subjected to 30% CR was reported to be slowed compared with that of AL controls [45]. ...
Calorie restriction (CR) has been shown to extend lifespan and retard aging-related functional decline in animals. Previously, we found that the anti-neoplastic and lifespan-extending effects of CR in mice are regulated by forkhead box O transcription factors (FoxO1 and FoxO3), located downstream of growth hormone (GH)–insulin-like growth factor (IGF)-1 signaling, in an isoform-specific manner. Inflammaging is a term coined to represent that persistent low-level of inflammation underlies the progression of aging and related diseases. Attenuation of inflammaging in the body may underlie the effects of CR. Recent studies have also identified cellular senescence and activation of the nucleotide-binding domain, leucine-rich-containing family, pyrin-domain-containing-3 (NLRP3) inflammasome as causative factors of inflammaging. In this paper, we reviewed the current knowledge of the molecular mechanisms linking the effects of CR with the formation of inflammasomes, particularly focusing on possible relations with FoxO3. Inflammation in the brain that affects adult neurogenesis and lifespan was also reviewed as evidence of inflammaging. A recent progress of microRNA research was described as regulatory circuits of initiation and propagation of inflammaging. Finally, we briefly introduced our preliminary results obtained from the mouse models, in which Foxo1 and Foxo3 genes were conditionally knocked out in the myeloid cell lineage.
... Human neural stem cells (hNSCs) are capable of generating neurons, oligodendrocytes and astrocytes, and can be found in the embryo and the ventricular-subventricular zone (V-SVZ) of the postnatal brain (Cavallucci et al., 2016;Gage, 2000;Storer et al., 2018). hNSCs can also be derived from human embryonic stem cells and share very similar properties with the in vivo counterparts. ...
... hNSCs are multipotent cells able to generate the neurons and glial cells of the central nervous system (Cavallucci et al., 2016;Ramos et al., 2015). They appear in the early stages of embryonic development and also reside in the ventricular-subventricular zone (V-SVZ) of the postnatal brain (Goncalves et al., 2016;Storer et al., 2018). ...
2′,2′,4,4′-tetrabromo diphenyl ether (BDE-47), one of the most abundant congeners of commercial pentaBDE utilized as flame retardants, has been phased out of production due to its potential neural toxicity and endocrine disrupting activities, and yet still present in the environment. Several alternatives to BDE-47, including tetrabromobisphenol A (TBBPA), tetrabromobisphenol S (TBBPS), tetrachlorobisphenol A (TCBPA) and decabromodiphenyl ether (BDE-209), are presently employed without restrictions and their potential toxic effects on human neural development are still unclear. In this study, we utilized a human neural stem cell (hNSC)-based system to evaluate the potential developmental neurotoxic effects of the above-mentioned five chemicals, at environment and human exposure relevant concentrations. We found that those compounds slightly altered the expression of hNSC identity markers (SOX2, SOX3 and NES), without impairing cell viability or proliferation, in part by either modulating glycogen synthase kinase 3 beta (GSK3β) signaling (TBBPS, TCBPA and BDE-47), and slightly disturbing the NOTCH pathway (TBBPA, TBBPS and TCBPA). Moreover, the five chemicals seemed to alter hNSC differentiation by perturbing triiodothyronine (T3) cellular signaling. Thus, our findings suggest that the five compounds, especially TBBPS, TCBPA, and BDE-47, may affect hNSC self-renewal and differentiation abilities and potentially elicit neural developmental toxicity.
... Quiescent and active stem cells are present in brain. NSCs is regulated due to changes in the microenvironment of niches (Cavallucci et al., 2016). The proliferative rate has been detected in the subventricular zone (SVZ), then the subgranular zone (SGZ) in rodents (Curtis et al., 2012). ...
Stem cell therapy is used for the treatment of many diseases like diabetes, ischemia, Parkinson’s disease, cardiac and neurodegenerative diseases. Stem cells can be differentiated into many new types as they are actually undifferentiated cells. Cardiac disease is a life-threatening disorder. Any type of injury to heart muscles increase risk factors for myocardial infarction. Studies indicate that different stem cells are used for the improvement of ventricular function by transplantation. New cardiac tissue cannot be formed but transplanted stem cells have paracrine effects that may be limited by teratoma formation. The brain has a specific formation of substitution connection to the confined and compact action of neuronal stem cells respectively. This demonstrates nervous abnormality and series of neurodegenerative infections that shows a critical civil issue of our inhabitants. So, competitive analysis is motivated using stem cell therapy as a key. Then comparisons of different studies for the treatment of different individuals who are suffering from neurodegenerative diseases are done. Different actions are taken that show aims for the charge of NP afflicted individuals. This review sums up the current scenario of stem cell therapy in Cardiac and Neurodegenerative disorders.
... Cell metabolism is strongly associated with stem cell identity and heterogeneity (13) and adapts to environmental and epigenetic factors (14). It has been shown that glycolysis supports the quiescence and multipotency, while activated mitochondrial oxidative phosphorylation (OXPHOS) is required for the differentiation of hematopoietic stem cells (HSCs) (15), mesenchymal stem cells (16), and neural stem cells (17). The preference for anaerobic glycolysis over OXPHOS was further proposed as the "metabolic stemness" for HSCs (15). ...
Tracking stem cell fate transition is crucial for understanding their development and optimizing biomanufacturing. Destructive single-cell methods provide a pseudotemporal landscape of stem cell differentiation but cannot monitor stem cell fate in real time. We established a metabolic optical metric using label-free fluorescence lifetime imaging microscopy (FLIM), feature extraction and machine learning–assisted analysis, for real-time cell fate tracking. From a library of 205 metabolic optical biomarker (MOB) features, we identified 56 associated with hematopoietic stem cell (HSC) differentiation. These features collectively describe HSC fate transition and detect its bifurcate lineage choice. We further derived a MOB score measuring the “metabolic stemness” of single cells and distinguishing their division patterns. This score reveals a distinct role of asymmetric division in rescuing stem cells with compromised metabolic stemness and a unique mechanism of PI3K inhibition in promoting ex vivo HSC maintenance. MOB profiling is a powerful tool for tracking stem cell fate transition and improving their biomanufacturing from a single-cell perspective.
... Other enriched GO terms were associated with metabolic processes and neuron death, critical mechanisms for neurogenesis progression and homeostasis 16,33,43 . We also identified genes with Cn SNPs that are important for later events in neurogenesis, such as migration, dendritogenesis, and maturation, according to the MANGO database. ...
Individuals with autism spectrum disorder (ASD) often exhibit atypical hippocampal anatomy and connectivity throughout their lifespan, potentially linked to alterations in the neurogenic process within the hippocampus. In this study, we performed an in-silico analysis to identify single-nucleotide polymorphisms (SNPs) in genes relevant to adult neurogenesis in the C58/J model of idiopathic autism. We found coding non-synonymous (Cn) SNPs in 33 genes involved in the adult neurogenic process, as well as in 142 genes associated with the signature genetic profile of neural stem cells (NSC) and neural progenitors. Based on the potential alterations in adult neurogenesis predicted by the in-silico analysis, we evaluated the number and distribution of newborn neurons in the dentate gyrus (DG) of young adult C58/J mice. We found a reduced number of newborn cells in the whole DG, a higher proportion of early neuroblasts in the subgranular layer (SGZ), and a lower proportion of neuroblasts with morphological maturation signs in the granule cell layer (GCL) of the DG compared to C57BL/6J mice. The observed changes may be associated with a delay in the maturation trajectory of newborn neurons in the C58/J strain, linked to the Cn SNPs in genes involved in adult hippocampal neurogenesis.
... The resting state of stem cells is identified as a key characteristic, regulation of which is performed by multiple mechanisms and is associated with the functions of self-maintenance, differentiation, and activation in response to damage [65,[74][75][76][77][78][79]. Disruption of regulation of the stem cells resting state is often accompanied by their depletion and is associated with the degenerative pathologies and aging [80][81][82][83]. ...
Immune privileges of cancer stem cells is a well-known and widely studied problem, as presence of such cells in tumors is associated with refractoriness, recurrence, and metastasis. Accumulating evidence also suggests presence of immune privileges in non-pathological stem cells in addition to their other defense mechanisms against damaging factors. This similarity between pathological and normal stem cells raises the question of why stem cells have such a potentially dangerous property. Regulation of vital processes of autoimmunity control and regeneration realized through interactions between immune cells, stem cells, and their microenvironment are reviewed in this work as causes of formation of the stem cell immune privilege. Deep mutual integration between regulations of stem and immune cells is noted. Considering diversity and complexity of mutual regulation of stem cells, their microenvironment, and immune system, I suggest the term “stem system”.
... Adult neurogenesis persists even at a lower rate in the subgranular zone (SGZ) of the hippocampus, the ventricular and subventricular zone of the lateral ventricle, along with the third ventricle and mediobasal hypothalamus (MBH). 81,82 NSCs in the SGZ could be vital for maintaining cognitive brain functions in old age; recent experimental studies have suggested that NSCs in the MBH regulate aging and lifespan in mice. [83][84][85] Our lifespan study in mice with heterozygous and homozygous whole-body Foxo3 gene knockout (Foxo3 +/and Foxo3 -/-) indicated that Foxo3 -/--AL mice showed 10% and 14% shorter lifespan at the 25th percentile survival point compared with Foxo3 +/--AL and Ctrl-AL mice, respectively. ...
Moderate restriction of dietary energy intake, referred to here as dietary restriction (DR), delays aging and extends lifespan in experimental animals compared with a diet of ad libitum feeding (AL) control animals. Basic knowledge of the mechanisms underlying the effects of DR could be applicable to extending the healthspan in humans. This review highlights the importance of forkhead box O (FoxO) transcription factors downstream of the growth hormone‐insulin‐like growth factor 1 signaling in the effects of DR. Our lifespan studies in mice with heterozygous Foxo1 or Foxo3 gene knockout indicated differential roles of FoxO1 and FoxO3 in the tumor‐inhibiting and life‐extending effects of DR. Subsequent studies suggested a critical role of FoxO3 in metabolic and mitochondrial bioenergetic adaptation to DR. Our studies also verified hypothalamic neuropeptide Y (Npy) as a vital neuropeptide showing pleiotropic and sexually dimorphic effects for extending the healthspan in the context of nutritional availability. Npy was necessary for DR to exert its effects in male and female mice; meanwhile, under AL conditions, the loss of Npy prevented obesity and insulin resistance only in female mice. Overnutrition disrupts FoxO‐ and Npy‐associated metabolic and mitochondrial bioenergetic adaptive processes, causing the acceleration of aging and related diseases.
... Adult NSPCs are mostly quiescent in vivo (Cavallucci et al., 2016). The balance between quiescence and activity regulates, not only the rate of cytogenesis, but also the long-term maintenance of the NSPC pool (Cheung and Rando, 2013;Urbán et al., 2019). ...
Postnatal neurogenesis has been shown to rely on the endocannabinoid system. Here we aimed at unravelling the role of Cannabidivarin (CBDV), a non-psychoactive cannabinoid, with high affinity for the non-classical cannabinoid receptor TRPV1, on subventricular zone (SVZ) postnatal neurogenesis. Using the neurosphere assay, SVZ-derived neural stem/progenitor cells (NSPCs) were incubated with CBDV and/or 5′-Iodoresinferotoxin (TRPV1 antagonist), and their role on cell viability, proliferation, and differentiation were dissected. CBDV was able to promote, through a TRPV1-dependent mechanism, cell survival, cell proliferation and neuronal differentiation. Furthermore, pulse-chase experiments revealed that CBDV-induced neuronal differentiation was a result of cell cycle exit of NSPCs. Regarding oligodendrocyte differentiation, CBDV inhibited oligodendrocyte differentiation and maturation. Since our data suggested that the CBDV-induced modulation of NSPCs acted via TRPV1, a sodium-calcium channel, and that intracellular calcium levels are known regulators of NSPCs fate and neuronal maturation, single cell calcium imaging was performed to evaluate the functional response of SVZ-derived cells. We observed that CBDV-responsive cells displayed a two-phase calcium influx profile, being the initial phase dependent on TRPV1 activation. Taken together, this work unveiled a novel and untapped neurogenic potential of CBDV via TRPV1 modulation. These findings pave the way to future neural stem cell biological studies and repair strategies by repurposing this non-psychoactive cannabinoid as a valuable therapeutic target.
... The tendency of stem cells to favor one fate decision over another is dependent on several intracellular and extracellular signaling cues. Stem cells are not constitutively active; rather, a quality control mechanism exists wherein a subset of stem cells enter quiescence, a state of metabolic depression, to maintain a functional pool of stem cells throughout adulthood [19]. Within this subset of metabolically inactive stem cells, there exist naïve and primed pluripotency states, which possess inherent epigenetic distinctions [20]. ...
The endocannabinoid system (ECS) governs and coordinates several physiological processes through an integrated signaling network, which is responsible for inducing appropriate intracellular metabolic signaling cascades in response to (endo)cannabinoid stimulation. This intricate cellular system ensures the proper functioning of the immune, reproductive, and nervous systems and is involved in the regulation of appetite, memory, metabolism, and development. Cannabinoid receptors have been observed on both cellular and mitochondrial membranes in several tissues and are stimulated by various classes of cannabinoids, rendering the ECS highly versatile. In the context of growth and development, emerging evidence suggests a crucial role for the ECS in cellular growth and differentiation. Indeed, cannabinoids have the potential to disrupt key energy-sensing metabolic signaling pathways requiring mitochondrial-ER crosstalk, whose functioning is essential for successful cellular growth and differentiation. This review aims to explore the extent of cannabinoid-induced cellular dysregulation and its implications for cellular differentiation.
... Increased mitochondrial protein folding stress during NSC activation and aging in the dentate gyrus Stem cell transition from quiescence to activation is associated with mitochondrial biogenesis and metabolic reprogramming from glycolysis to mitochondrial metabolism. 37 Increased mitochondrial biogenesis and activity is associated with the mitochondrial protein folding stress. 38,39 The analysis of single-cell RNA sequencing data for the dentate gyrus of young and old mice showed that the mitochondrial chaperone HSP60 was expressed remarkably in activated NSCs/NPCs among all cell populations in the dentate gyrus ( Figure 2A). ...
Aging results in a decline in neural stem cells (NSCs), neurogenesis, and cognitive function, and evidence is emerging to demonstrate disrupted adult neurogenesis in the hippocampus of patients with several neurodegenerative disorders. Here, single-cell RNA sequencing of the dentate gyrus of young and old mice shows that the mitochondrial protein folding stress is prominent in activated NSCs/neural progenitors (NPCs) among the neurogenic niche, and it increases with aging accompanying dysregulated cell cycle and mitochondrial activity in activated NSCs/NPCs in the dentate gyrus. Increasing mitochondrial protein folding stress results in compromised NSC maintenance and reduced neurogenesis in the dentate gyrus, neural hyperactivity, and impaired cognitive function. Reducing mitochondrial protein folding stress in the dentate gyrus of old mice improves neurogenesis and cognitive function. These results establish the mitochondrial protein folding stress as a driver of NSC aging and suggest approaches to improve aging-associated cognitive decline.
... Cellular metabolism has been shown to determine the activity state of stem cells (3,4), and metabolic features appear similar among different tissue-specific adult stem cells. In general, stem cells are rather glycolytic to support synthesis of cellular building blocks to sustain cell growth, while during differentiation, their metabolic profile shifts toward oxidative metabolism to generate adenosine triphosphate (5)(6)(7)(8)(9)(10)(11)(12)(13). ...
Cellular metabolism is important for adult neural stem/progenitor cell (NSPC) behavior. However, its role in the transition from quiescence to proliferation is not fully understood. We here show that the mitochondrial pyruvate carrier (MPC) plays a crucial and unexpected part in this process. MPC transports pyruvate into mitochondria, linking cytosolic glycolysis to mitochondrial tricarboxylic acid cycle and oxidative phosphorylation. Despite its metabolic key function, the role of MPC in NSPCs has not been addressed. We show that quiescent NSPCs have an active mitochondrial metabolism and express high levels of MPC. Pharmacological MPC inhibition increases aspartate and triggers NSPC activation. Furthermore, genetic Mpc1 ablation in vitro and in vivo also activates NSPCs, which differentiate into mature neurons, leading to overall increased hippocampal neurogenesis in adult and aged mice. These findings highlight the importance of metabolism for NSPC regulation and identify an important pathway through which mitochondrial pyruvate import controls NSPC quiescence and activation.
... Aging is associated with impaired neurogenesis, specifically decreased self-renewal, proliferation, and capacity for regenerating neurons to integrate into the central nervous system network (Cavallucci et al., 2016). Aging-associated reductions in hippocampal and olfactory neurogenesis contribute to corresponding cognitive and olfactory decline (Lazarov et al., 2010). ...
... Systemic and local signals seem to regulate NSC quiescence by modulating the expression or function of molecules acting within stem cells. These include transcription factors, cell cycle regulators, and metabolites, which in turn control NSC quiescence or activation (Cavallucci et al., 2016;Kippin et al., 2005;Knobloch et al., 2017;Sueda et al., 2019). Although several molecular players in the regulation of NSC quiescence have been reported (Ahn and Joyner, 2005;Chavali et al., 2018;Engler et al., 2018;Ganapathi et al., 2018;Kandasamy et al., 2014;Marqués-Torrejó n et al., 2021;Sueda et al., 2019;Urbán et al., 2019), we know remarkably little about the direct determinants of quiescence and the mechanisms of the transition between active and quiescent states in NSCs. ...
Cellular quiescence facilitates maintenance of neural stem cells (NSCs) and their subsequent regenerative functions in response to brain injury and aging. However, the specification and maintenance of NSCs in quiescence from embryo to adulthood remain largely unclear. Here, using Set domain-containing protein 4 (SETD4), an epigenetic determinant of cellular quiescence, we mark a small but long-lived NSC population in deep quiescence in the subventricular zone of adult murine brain. Genetic lineage tracing shows that SETD4⁺ cells appear before neuroectoderm formation and contribute to brain development. In the adult, conditional knockout of Setd4 resulted in quiescence exit of NSCs, generating newborn neurons in the olfactory bulb and contributing to damage repair. However, long period deletion of SETD4 lead to exhaustion of NSC reservoir or SETD4 overexpression caused quiescence entry of NSCs, leading to suppressed neurogenesis. This study reveals the existence of long-lived deep quiescent NSCs and their neurogenetic capacities beyond activation.
... In the NSCs population, a small fraction of type-1 NSCs symmetrically divide into self-renewal cells, and 70% to 80% of type-1 NSCs are consumed by the asymmetric generation of type-2 cells. This results in the depletion of type-1 cells over time [41,43,44]. We noticed that maternal HFD induced a dramatic reduction in type-2 NSCs (non-radial Nestin + ) during DG development. ...
Maternal obesity or exposure to a high-fat diet (HFD) has an irreversible impact on the structural and functional development of offspring brains. This study aimed to investigate whether maternal HFD during pregnancy and lactation impairs dentate gyrus (DG) neurogenesis in offspring by altering neural stem cells (NSCs) behaviors. Pregnant Sprague-Dawley rats were fed a chow diet (CHD) or HFD (60% fat) during gestation and lactation. Pups were collected on postnatal day 1 (PND 1), PND 10 and PND 21. Changes in offspring body weight, brain structure and granular cell layer (GCL) thickness in the hippocampus were analyzed. Hippocampal NSCs behaviors, in terms of proliferation and differentiation, were investigated after immunohistochemical staining with Nestin, Ki67, SOX2, Doublecortin (DCX) and NeuN. Maternal HFD accelerated body weight gain and brain structural development in offspring after birth. It also reduced the number of NSCs and their proliferation, leading to a decrease in NSCs pool size. Furthermore, maternal HFD intensified NSCs depletion and promoted neuronal differentiation in the early postnatal development period. These findings suggest that maternal HFD intake significantly reduced the amount and capability of NSCs via reducing type–2 NSCs and promoting premature neuronal differentiation during postnatal hippocampal development.
... Cellular metabolism has been shown to determine the activity state of stem cells (Cavallucci et al., 2016;Ly et al., 2020) and metabolic features appear similar among different tissue-specific adult stem cells. Quiescence is considered as a state in which stem cells mainly use glycolysis to sustain their energy demand. ...
Cellular metabolism is important for adult neural stem/progenitor cell (NSPC) behavior. However, its role in the transition from quiescence to proliferation is not fully understood. We here show that the mitochondrial pyruvate carrier (MPC) plays a crucial and unexpected part in this process. MPC transports pyruvate into mitochondria, linking cytosolic glycolysis to mitochondrial tricarboxylic acid cycle (TCA) and oxidative phosphorylation (OXPHOS). Despite its metabolic key function, the role of MPC in NSPCs has not been addressed. We show that quiescent NSPCs have an active mitochondrial metabolism and express high levels of MPC. Pharmacological MPC inhibition increases aspartate and triggers NSPC activation. Furthermore, genetic MPC-ablation in vivo also activates NSPCs, which differentiate into mature neurons, leading to overall increased hippocampal neurogenesis in adult and aged mice. These findings highlight the importance of metabolism for NSPC regulation and identify a novel pathway through which mitochondrial pyruvate import controls NSPC quiescence and activation.
Highlights
• Quiescent NSPCs have high levels of MPC and an active mitochondrial network
• The import of pyruvate into mitochondria is necessary to maintain quiescence of NSPCs
• MPC inhibition increases intracellular aspartate levels and triggers the activation of quiescent NSPCs
• MPC-knockout NSPCs generate mature newborn neurons, leading to overall increased neurogenesis in adult and advanced age mice
Graphical abstract
... Additionally, extrinsic and intrinsic cues together coordinate NSC proliferation with niche and systemic growth. Similar regulatory mechanisms involving extracellular and cellular components of the niche, as well as humoral cues and nutrients have also been showed to influence the behaviour of NSCs in the mammalian CNS [161,162]. In spite of these insights, some knowledge gaps remain. ...
The formation of a functional circuitry in the central nervous system (CNS) requires the correct number and subtypes of neural cells. In the developing brain, neural stem cells (NSCs) self-renew while giving rise to progenitors that in turn generate differentiated progeny. As such, the size and the diversity of cells that make up the functional CNS depend on the proliferative properties of NSCs. In the fruit fly Drosophila, where the process of neurogenesis has been extensively investigated, extrinsic factors such as the microenvironment of NSCs, nutrients, oxygen levels and systemic signals have been identified as regulators of NSC proliferation. Here, we review decades of work that explores how extrinsic signals non-autonomously regulate key NSC characteristics such as quiescence, proliferation and termination in the fly.
... In order to prevent NSCs from premature exhaustion, qNSCs present the expression of the cyclin-dependent kinases-p57, p27, and p21. A similar role was shown for chromodomain helicase DNA-binding protein 7(CHD7) [24][25][26][27]. NSC quiescence maintenance is also provided by a balanced activation of canonical and noncanonical WNT activity. ...
Rapid developments in stem cell research in recent years have provided a solid foundation for their use in medicine. Over the last few years, hundreds of clinical trials have been initiated in a wide panel of indications. Disorders and injuries of the nervous system still remain a challenge for the regenerative medicine. Neural stem cells (NSCs) are the optimal cells for the central nervous system restoration as they can differentiate into mature cells and, most importantly, functional neurons and glial cells. However, their application is limited by multiple factors such as difficult access to source material, limited cells number, problematic, long and expensive cultivation in vitro, and ethical considerations. On the other hand, according to the available clinical databases, most of
the registered clinical trials involving cell therapies were carried out with the use of mesenchymal stem/stromal/signalling cells (MSCs) obtained from afterbirth or adult human somatic tissues. MSCs are the multipotent cells which can also differentiate into neuron-like and glia-like cells under proper conditions in vitro; however, their main therapeutic effect is more associated with secretory and supportive properties. MSCs, as a natural component of cell niche, affect the environment through immunomodulation as well as through the secretion of the trophic factors. In this review, we discuss various therapeutic strategies and activated mechanisms related to bilateral MSC–NSC interactions, differentiation of MSCs towards the neural cells (subpopulation of crest-derived cells) under the environmental conditions, bioscaffolds, or co-culture with NSCs by recreating the conditions of the neural cell niche.
... Quiescence, typically thought of as G0 arrest, is associated with reduced transcription, translation and ribosome biogenesis and, more recently, with increased lysosomal activity and fatty acid utilization (Kalucka et al., 2018;Coller, 2019;Kobayashi et al., 2019). In adults, stem cells reactivate from quiescence to maintain tissue homeostasis and for repair, whereas in development, quiescence is 'pre-programmed' and required to ensure that sufficient dietary nutrients or other key factors are available to fuel cell divisions needed to support continued growth (Cheung and Rando, 2013;Cavallucci et al., 2016;Kalamakis et al., 2019;Cho et al., 2019;Urbán et al., 2019). Although stem cell entry and exit from quiescence is important in development and adulthood, mechanisms and the cell signaling pathways that regulate quiescence entry and exit are incompletely understood (Li et al., 2017;Mohammad et al., 2019;Sueda and Kageyama, 2020). ...
Stem cells enter and exit quiescence as part of normal developmental programs and to maintain tissue homeostasis in adulthood. While it is clear that stem cell intrinsic and extrinsic cues, local and systemic, regulate quiescence, it remains unclear whether intrinsic and extrinsic cues coordinate to control quiescence and how cue coordination is achieved. Here, we report that Notch signaling coordinates neuroblast intrinsic temporal programs with extrinsic nutrient cues to regulate quiescence in Drosophila. When Notch activity is reduced, quiescence is delayed or altogether bypassed, with some neuroblasts dividing continuously during the embryonic to larval transition. During embryogenesis before quiescence, neuroblasts express Notch and the Notch ligand, Delta. After division, Delta is partitioned to adjacent GMC daughters where it transactivates Notch in neuroblasts. Over time in response to intrinsic temporal cues and increasing numbers of Delta-expressing daughters, neuroblast Notch activity increases leading to cell cycle exit and consequently, attenuation of Notch pathway activity. Quiescent neuroblasts have low to no active Notch, which is required for exit from quiescence in response to nutrient cues. Thus, Notch signaling coordinates proliferation versus quiescence decisions.
... When it occurs in adult life, it is known as adult neurogenesis (AN). Although NSCs are present in several brain regions, the subgranular zone of the hippocampus and the subventricular zone of the lateral ventricle are the main AN niches [15]. AN in other adult brain regions (e.g., the neocortex, striatum, amygdala and substantia nigra) is limited under normal physiological conditions, but could be induced after injury [16]. ...
Adult neurogenesis (i.e., the life-long generation of new neurons from undifferentiated neuronal precursors in the adult brain) may contribute to brain repair after damage, and participates in plasticity-related processes including memory, cognition, mood and sensory functions. Among the many intrinsic (oxidative stress, inflammation, and ageing), and extrinsic (environmental pollution, lifestyle, and diet) factors deemed to impact neurogenesis, significant attention has been recently attracted by the myriad of saprophytic microorganismal communities inhabiting the intestinal ecosystem and collectively referred to as the gut microbiota. A growing body of evidence, mainly from animal studies, reveal the influence of microbiota and its disease-associated imbalances on neural stem cell proliferative and differentiative activities in brain neurogenic niches. On the other hand, the long-claimed pro-neurogenic activity of natural dietary compounds endowed with antioxidants and anti-inflammatory properties (such as polyphenols, polyunsaturated fatty acids, or pro/prebiotics) may be mediated, at least in part, by their action on the intestinal microflora. The purpose of this review is to summarise the available information regarding the influence of the gut microbiota on neurogenesis, analyse the possible underlying mechanisms, and discuss the potential implications of this emerging knowledge for the fight against neurodegeneration and brain ageing.
... Due to the poor survival of the mutants beyond 12 mpf, we cannot address the consequences of these proliferative changes for retinal maintenance in later adult stages. Our results are further consistent with reports that chronic hyperglycemia disrupts neurogenesis and negatively impacts the maintenance of neural stem and progenitor cells [58,59]. ...
Diabetic retinopathy is a frequent complication of longstanding diabetes, which comprises a complex interplay of microvascular abnormalities and neurodegeneration. Zebrafish harboring a homozygous mutation in the pancreatic transcription factor pdx1 display a diabetic phenotype with survival into adulthood, and are therefore uniquely suitable among zebrafish models for studying pathologies associated with persistent diabetic conditions. We have previously shown that, starting at three months of age, pdx1 mutants exhibit not only vascular but also neuro-retinal pathologies manifesting as photoreceptor dysfunction and loss, similar to human diabetic retinopathy. Here, we further characterize injury and regenerative responses and examine the effects on progenitor cell populations. Consistent with a negative impact of hyperglycemia on neurogenesis, stem cells of the ciliary marginal zone show an exacerbation of aging-related proliferative decline. In contrast to the robust Müller glial cell proliferation seen following acute retinal injury, the pdx1 mutant shows replenishment of both rod and cone photoreceptors from slow-cycling, neurod-expressing progenitors which first accumulate in the inner nuclear layer. Overall, we demonstrate a diabetic retinopa-thy model which shows pathological features of the human disease evolving alongside an ongoing restorative process that replaces lost photoreceptors, at the same time suggesting an unappreciated phenotypic continuum between multipotent and photoreceptor-committed progenitors.
... Metabolically, NSCs depend on glycolysis to maintain its stemness, but its differentiation is involved in the activation of several metabolic pathways including elevated fatty acid consumption, increased lipogenesis, decreased glycolysis and activated OXPHOS. [120][121][122] This metabolic phenotype transition during NSCs differentiation is similar to the PMT. Glycolysis dependent type C cells show tolerance to the hypoxia environment, 123 but its proliferation still relies on absorbing extracellular fatty acid and activating de novo lipogenesis. ...
Glioblastoma is the most malignant tumor occurring in the human central nervous system with overall median survival time <14.6 months. Current treatments such as chemotherapy and radiotherapy cannot reach an optimal remission since tumor resistance to therapy remains a challenge. Glioblastoma stem cells are considered to be responsible for tumor resistance in treating glioblastoma. Previous studies reported two subtypes, proneural and mesenchymal, of glioblastoma stem cells manifesting different sensitivity to radiotherapy or chemotherapy. Mesenchymal glioblastoma stem cells, as well as tumor cells generate from which, showed resistance to radiochemotherapies. Besides, two metabolic patterns, glutamine or glucose dependent, of mesenchymal glioblastoma stem cells also manifested different sensitivity to radiochemotherapies. Glutamine dependent mesenchymal glioblastoma stem cells are more sensitive to radiotherapy than glucose-dependent ones. Therefore, the transition between proneural and mesenchymal subtypes, or between glutamine-dependent and glucose-dependent, might lead to tumor resistance to radiochemotherapies. Moreover, neural stem cells were also hypothesized to participate in glioblastoma stem cells mediated tumor resistance to radiochemotherapies. In this review, we summarized the basic characteristics, adaptive transition and implications of glioblastoma stem cells in glioblastoma therapy.
... However, we lack detailed information on how these system level changes are translated to the neural precursor cells (NPCs) residing in the hippocampus. In this context, the availability of metabolites (Cavallucci et al. 2016) and the cellular energetic state (Knobloch et al. 2013;Beckervordersandforth et al. 2017) represent important factors that have an effect on NPC behavior and plasticity in the adult hippocampus and are potentially modifiable by 'lifestyle interventions', such as exercise. In this context, the beneficial effects of exercise and learning stimuli on adult hippocampal neurogenesis have been positively associated to the availability of the metabolite L-lactate (El Hayek et al. 2019;Lev-Vachnish et al. 2019). ...
L-lactate has energetic and signaling properties and its availability is modulated by activity-dependent stimuli, which also regulate adult hippocampal neurogenesis. Studying the effects of L-lactate on neural precursor cells (NPCs) in vitro, we found that L-lactate is pro-proliferative and that this effect is dependent on the active lactate transport by monocarboxylate transporters. Increased proliferation was not linked to amplified mitochondrial respiration. Instead, L-lactate deviated glucose metabolism to the pentose phosphate pathway, indicated by increased glucose-6-phosphate dehydrogenase activity while glycolysis decreased. Knockout of Hcar1 revealed that the pro-proliferative effect of L-lactate was not dependent on receptor activity although phosphorylation of ERK1/2 and Akt was increased following L-lactate treatment. Together, we show that availability of L-lactate is linked to the proliferative potential of NPCs and add evidence to the hypothesis that lactate influences cellular homeostatic processes in the adult brain, specifically in the context of adult hippocampal neurogenesis.
... Therefore, neurogenesis decline may result from direct brain damage and inflammation (Gould and Tanapat, 1997;Parent et al., 1997), but also from premature neuronal differentiation processes, followed by depletion of the active NSC pool in the brain, as our results suggest. In fact, neurogenesis has already been shown to be triggered during metabolic disorders and/or upon HFD, where the switch of quiescent NSCs into activated NSCs leads to premature exhaustion of NSC (Cavallucci et al., 2016). ...
The influence of dietary factors on brain health and mental function is becoming increasingly recognized. Similarly, mounting evidence supports a role for gut microbiota in modulating central nervous system function and behaviour. Still, the molecular mechanisms responsible for the impact of diet and associated microbiome in adult neurodegeneration are still largely unclear. In this study, we aimed to investigate whether and how changes in diet-associated microbiome and its metabolites impact on adult neurogenesis. Mice were fed a high-fat, choline-deficient diet, developing obesity and several features of the metabolic syndrome, including non-alcoholic steatohepatitis. Strikingly, our results showed, for the first time, that animals fed with this specific diet display premature increased neurogenesis, possibly exhausting the available neural stem cell pool for long-term neurogenesis processes. The high-fat, choline-deficient diet further induced neuroinflammation, oxidative stress, synaptic loss and cell death in different regions of the brain. Notably, this diet-favoured gut dysbiosis in the small intestine and cecum, up-regulating metabolic pathways of short-chain fatty acids, such as propionate and butyrate and significantly increasing propionate levels in the liver. By dissecting the effect of these two specific short-chain fatty acids in vitro, we were able to show that propionate and butyrate enhance mitochondrial biogenesis and promote early neurogenic differentiation of neural stem cells through reactive oxygen species- and extracellular signal-regulated kinases 1/2-dependent mechanism. More importantly, neurogenic niches of high-fat, choline-deficient-fed mice showed increased expression of mitochondrial biogenesis markers, and decreased mitochondrial reactive oxygen species scavengers, corroborating the involvement of this mitochondrial stress-dependent pathway in mediating changes of adult neurogenesis by diet. Altogether, our results highlight a mitochondria-dependent pathway as a novel mediator of the gut microbiota–brain axis upon dietary influences.
... Diet is another environmental factor that has been shown to influence the neurogenic process (Stangl and Thuret, 2009;Miquel et al., 2018;Abbink et al., 2020). Drosophila research shows that nutritional factors can influence the exit of neural hippocampal progenitors from quiescence (Chell and Brand, 2010;Spéder and Brand, 2014), and other nutritional-based changes to the hippocampal progenitor pool have been likewise demonstrated across other species (Spéder et al., 2011;Sakayori et al., 2013;Cavallucci et al., 2016). For instance, in humans, the nutrient-sensing pathways: the mammalian target of rapamycin (mTOR), sirtuin, and insulin-like growth factor 1, have all been associated with hippocampal progenitor maintenance (de Lucia et al., 2020). ...
The age-associated reduction in the proliferation of neural stem cells (NSCs) has been associated with cognitive decline. Numerous factors have been shown to modulate this process, including dietary components. Frequent consumption of caffeine has been correlated with an increased risk of cognitive decline, but further evidence of a negative effect on hippocampal progenitor proliferation is limited to animal models. Here, we used a human hippocampal progenitor cell line to investigate the effects of caffeine on hippocampal progenitor integrity and proliferation specifically. The effects of five caffeine concentrations (0 mM = control, 0.1 mM ∼ 150 mg, 0.25 mM ∼ 400 mg, 0.5 mM ∼ 750 mg, and 1.0 mM ∼ 1500 mg) were measured following acute (1 day) and repeated (3 days) exposure. Immunocytochemistry was used to quantify hippocampal progenitor integrity (i.e., SOX2- and Nestin-positive cells), proliferation (i.e., Ki67-positive cells), cell count (i.e., DAPI-positive cells), and apoptosis (i.e., CC3-positive cells). We found that progenitor integrity was significantly reduced in supraphysiological caffeine conditions (i.e., 1.0 mM ∼ 1500 mg), but relative to the lowest caffeine condition (i.e., 0.1 mM ∼ 150 mg) only. Moreover, repeated exposure to supraphysiological caffeine concentrations (i.e., 1.0 mM ∼ 1500 mg) was found to affect proliferation, significantly reducing % Ki67-positive cells relative to control and lower caffeine dose conditions (i.e., 0.1 mM ∼ 150 mg and 0.25 mM ∼ 400 mg). Caffeine treatment did not influence apoptosis and there were no significant differences in any measure between lower doses of caffeine (i.e., 0.1 mM, 0.25 mM, 0.5 mM) – representative of daily human caffeine intake – and control conditions. Our study demonstrates that dietary components such as caffeine can influence NSC integrity and proliferation and may be indicative of a mechanism by which diet affects cognitive outcomes.
... Once an arbitrary threshold is surpassed, where the levels of accumulated mtDNA mutations surpass normal/healthy mtDNA, energy metabolism is impaired (Figure 2; Wallace, 2010). This is significant in tissues with high energy demands such as the NSC niches of the developing and injured adult brain (Cavallucci et al., 2016). mtDNA integrity is maintained via repair machinery such as 8-oxoguanine DNA glycosylase (OGG1), a DNA repair protein that restores damaged mtDNA. ...
The adult central nervous system (CNS) contains resident stem cells within specific niches that maintain a self-renewal and proliferative capacity to generate new neurons, astrocytes, and oligodendrocytes throughout adulthood. Physiological aging is associated with a progressive loss of function and a decline in the self-renewal and regenerative capacities of CNS stem cells. Also, the biggest risk factor for neurodegenerative diseases is age, and current in vivo and in vitro models of neurodegenerative diseases rarely consider this. Therefore, combining both aging research and appropriate interrogation of animal disease models towards the understanding of the disease and age-related stem cell failure is imperative to the discovery of new therapies. This review article will highlight the main intrinsic and extrinsic regulators of neural stem cell (NSC) aging and discuss how these factors impact normal homeostatic functions within the adult brain. We will consider established in vivo animal and in vitro human disease model systems, and then discuss the current and future trajectories of novel senotherapeutics that target aging NSCs to ameliorate brain disease.
... The specific proteins in these aggregates could also participate in NSC defects, but the composition of the protein aggregates in young and old NSCs remains entirely unknown. Integration of Nutrient-Sensing, Metabolism, and Proteostasis Pathways in NSCs Overall, the different metabolic and proteostatic strategies used by qNSCs and aNSCs and their progeny are likely necessary to support the fundamental functional differences between these cell types ( Figure 2; see reviews by Cavallucci et al., 2016;Knobloch and Jessberger, 2017). Dormant, non-dividing qNSCs have lower metabolic demands and employ mechanisms to produce energy long term, such as the lysosome-autophagy pathway and FAO. ...
Aging has a profound and devastating effect on the brain. Old age is accompanied by declining cognitive function and enhanced risk of brain diseases, including cancer and neurodegenerative disorders. A key question is whether cells with regenerative potential contribute to brain health and even brain “rejuvenation.” This review discusses mechanisms that regulate neural stem cells (NSCs) during aging, focusing on the effect of metabolism, genetic regulation, and the surrounding niche. We also explore emerging rejuvenating strategies for old NSCs. Finally, we consider how new technologies may help harness NSCs’ potential to restore healthy brain function during physiological and pathological aging.
... Indeed, many populations of adult stem cells including hematopoietic, muscle, and neural stem cells are primarily in a nonproliferating quiescent state of G 0 (Cho et al. 2019; van Velthoven and Rando 2019). Evidence suggests that quiescence serves a protective role in these contexts as these populations of stem cells become depleted or "exhausted" when driven into the cell cycle on transplantation, caused by stress, or on genetic manipulation (Harrison 1978;Chen et al. 2000;Kamminga et al. 2006;Gan et al. 2010;Sacco et al. 2010;Schaniel et al. 2011;Staber et al. 2013;Cavallucci et al. 2016;Yue et al. 2016;Baumgartner et al. 2018;Singh et al. 2018). Stem cell exhaustion in these contexts may be a result of the loss of niche signals. ...
Adult stem cells fuel tissue homeostasis and regeneration through their unique ability to self-renew and differentiate into specialized cells. Thus, their DNA provides instructions that impact the tissue as a whole. Since DNA is not an inert molecule, but rather dynamic, interacting with a myriad of chemical and physical factors, it encounters damage from both endogenous and exogenous sources. Damage to DNA introduces deviations from its normal intact structure and, if left unrepaired, may result in a genetic mutation. In turn, mutant genomes of stem and progenitor cells are inherited in cells of the lineage, thus eroding the genetic information that maintains homeostasis of the somatic cell population. Errors arising in stem and progenitor cells will have a substantially larger impact on the tissue in which they reside than errors occurring in postmitotic differentiated cells. Therefore, maintaining the integrity of genomic DNA within our stem cells is essential to protect the instructions necessary for rebuilding healthy tissues during homeostatic renewal. In this review, we will first discuss DNA damage arising in stem cells and cell- and tissue-intrinsic mechanisms that protect against harmful effects of this damage. Secondly, we will examine how erroneous DNA repair and persistent DNA damage in stem and progenitor cells impact stem cells and tissues in the context of cancer initiation and aging. Finally, we will discuss the use of invertebrate and vertebrate model systems to address unanswered questions on the role that DNA damage and mutation may play in aging and precancerous conditions.
... Neurogenic niches are characterized by low oxygen tension and, not by chance, an elevated anaerobic glycolytic activity is associated with neural stemness. During differentiation, instead, oxidative phosphorylation becomes predominant [9,10]. Adult hippocampal neurogenic lineage is strongly dependent on the mitochondrial electron transport chain and oxidative phosphorylation during the fast proliferating progenitor cell phase and the disruption of mitochondrial function inhibits neurogenesis at NPC stage and reproduces aging-like phenotypes [11 ]. ...
Adult neurogenesis, the generation of mature functional neurons from neural stem cells in specific regions of the adult mammalian brain, is implicated in brain physiology, neurodegeneration and mood disorders. Among the many intrinsic and extrinsic factors that modulate neurogenic activity, the role of nutrients, energy metabolism, and gut microbiota has recently emerged. It is increasingly evident that excessive calorie intake accelerates the age-dependent decline of neurogenesis, while calorie restriction and physical exercise have the opposite effect. Mechanistically, nutrient availability could affect neurogenesis by modulating autophagy, a cell-rejuvenating process, in neural stem cells. In parallel, diet can alter the composition of gut microbiota thus impacting the intestine-neurogenic niche communication. These exciting breakthroughs are here concisely reviewed.
... Similarly, a lack of vascularization will result in the same issues in vivo. Stem cells in particular heavily rely on nutrients to regulate their transition between a quiescent and activated state, as entry into the cell cycle requires high amounts of energy (Cavallucci, et al., 2016). As such, not only can a lack of nutrients cause starvation, but it can also influence behavior such as proliferation and differentiation. ...
The field of tissue engineering is making great strides in developing replacement tissue grafts for clinical use, marked by the rapid development of novel biomaterials, their improved integration with cells, better‐directed growth and differentiation of cells, and improved 3D tissue mass culturing. One major obstacle that remains, however, is the lack of graft vascularization, which in turn renders many grafts to fail upon clinical application. With that, graft vascularization has turned into one of the holy grails of tissue engineering, and for the majority of tissues it will be imperative to achieve adequate vascularization if tissue graft implantation is to succeed. Many different approaches have been developed to induce or augment graft vascularization, both in vitro and in vivo. In this review, we highlight the importance of vascularization in tissue engineering, and outline various approaches inspired by both biology and engineering to achieve and augment graft vascularization.
Aging is the major danger agent for many age-related disorders, including neurological diseases. Knowing the biological mechanisms of aging is critical to achieve brain health. In this regard, brain aging is characterized by neurophysiological functions gradually decline, impaired adaptive neuroplasticity, dysregulation of neuronal calcium homeostasis, neuroinflammation, and oxidatively modified molecules and organelles. Several molecular and cellular indicators of brain aging include mitochondrial dysfunction, accumulation of oxidatively damaged molecules, impaired lysosome and proteasome function, dysregulation of neuronal calcium homeostasis, inflammation, and impaired neurogenesis. Thus, therapeutic approaches target the beneficial effects of phytochemicals on aging-associated impairment of brain function. In cellular models of neurological diseases, phytochemicals, or food’s second metabolites, preserve neuronal cells against cell death, and the neuroprotective effect is attributed to antioxidant, antiinflammatory, and antiaging properties. Phytochemicals activate the neuronal antioxidant defense and survival. Mechanisms associated with neuroprotective effects of phytochemicals on the brain such as cellular defense against oxidative stress (the Nrf2-ARE antioxidant system), cell survival system (the TrkB signaling pathway), and crosstalk between TrkB signaling pathway and Nrf2-ARE antioxidant system were outlined. The recent evidence in this chapter describes the hallmarks of brain aging which affect impairment in brain function, acknowledgment of antiaging, antioxidant, and antiinflammatory effects of phytochemicals against oxidative stress and emphasizes their importance as a protective agent for brain aging and neurodegenerative disease resistance.
The immune privileges of cancer stem cells are a well-known and widely studied problem, as the presence of such cells in tumors is associated with refractoriness, recurrence, and metastasis. Accumulating evidence also suggests the presence of immune privileges for non-pathologic stem cells in addition to their other defense mechanisms against damaging factors. This similarity between pathologic and normal stem cells raises the question of why stem cells have such a potentially damaging property. The regulation of vital processes of autoimmunity control and regeneration by interactions between immune cells, stem cells and their microenvironment are reviewed as determinants of stem cell immune privilege formation. A deep mutual integration in the regulation of stem and immune cells is noted. Based on the diversity and complexity of the mutual regulation of stem cells, their microenvironment and the immune system, I propose to use the term “stem system”.
Stem cells with self-renewal and multi-lineage differentiation potential have potential for developing medicines for a range of refractory and recurrent disease. This book mainly focuses on the landscape of the biological properties and translational research of stem cells types, including hematopoietic stem cells (HSCs), neural stem cells (NSCs) and mesenchymal stem/stromal cells (MSCs).
The book also introduces readers to the current updates and development prospects of stem cells in singular or combination therapies with advanced biomaterials and technological innovations towards large-scale standardization and productization.
T-Cell Factors (TCFs) are the main transcriptional effectors of Wnt/beta-catenin signaling. TCF responsiveness is a hallmark of self-renewal in mouse embryonic, and adult, neural stem cells (NSC). However, in vivo contribution(s) of TCF activities in long-lived NSCs are poorly understood. Granule neuron progenitors (GNP) in the upper rhombic lip (URL) are long-lived NSCs which express Atoh1 and generate cerebellar granule neurons. Using functional and transcriptomic approaches in amphibian, we demonstrate that TCFs are active in the URL, and are strictly necessary for the emergence and maintenance of the GNP germinative zone. We identify BarH-like 1 (Barhl1), a direct target of Atoh1, as a gate keeper for GNP exit from the URL, through silencing of TCF transcriptional activity. Our transcriptomic and in silico analysis identifies Barhl1/TCF URL target genes, and confirms our functional data. Our study provides in vivo evidence that inhibition of TCF repressive activity is necessary for maintenance of the URL, a long-lived neural germinative niche.
https://www.mdpi.com/books/book/6617-induced-impairment-of-neurogenesis-and-brain-diseases
Overfeeding (OF) and obesity increase the risk for brain aging and neurodegenerative diseases due to increased oxidative stress and neuroinflammation, which likely contribute to cellular dysfunction. In contrast, caloric restriction (CR) is an intervention known for its effects on extending both life- and health-span. In the current study, the effects on the aging brain of two short-term feeding regimens, OF and CR, were investigated. We applied these diets for 12 weeks to both young and aged zebrafish. We performed protein and mRNA level analysis to examine diet-mediated effects on any potential age-related alterations in the brain. Markers implicated in the regulation of brain aging, cell cycle, proliferation, inflammation, and cytoskeleton were analyzed. The most prominent result observed was a downregulation in the expression levels of the stem cell marker, Sox2, in CR-fed animals as compared to OF-fed fish. Furthermore, our data highlighted significant age-related downregulations in Tp53, Myca, and L-plastin levels. The multivariate analyses of all datasets suggested that as opposed to OF, the adaptive mechanisms increasing lifespan via CR are likely exerting their effects by reinforcing the stem cell pool and downregulating inflammation. The data reveal important therapeutic targets with respect to the state of nutrient uptake for the slowing down of the detrimental effects of aging, resulting in a healthy and extended lifespan, as well as lowering the risk for neurodegenerative disease.
Different types of traumatic brain injury (TBI) have posed a hazard to human health for a while, and their aftereffects have a significant negative impact on patients' quality of life. Despite the increased attention that TBI has received recently, the clinical treatment plan that is currently in place only consists of palliative therapy for neuroprotection or the mitigation of secondary injury, which has only a minimally positive impact on the prognosis and quality of life in TBI patients. After TBI, regenerative therapy seeks to improve the patient's function. Cell therapy, which has become one of the hottest research fields, is expected to improve the therapeutic effect of this disease. This article will briefly discuss recent developments in research of TBI and available treatments, and then give a general assessment of the outlook.
Ubiquitin-specific protease 22 (USP22), a potential marker of cancer stem cells, significantly influences stem cell fate choices. However, its functions in neural stem cells (NSCs) and adult neurogenesis, especially following traumatic brain injury (TBI), remain only partially understood. Here, we found that aberrant USP22 expression could affect NSC proliferation and stemness maintenance, as assessed by the generation of neurospheres, cell counting kit-8 (CCK-8) and immunofluorescence staining in vitro. Moreover, USP22 depletion promotes the differentiation of NSCs, both in vitro and in vivo. In contrast, USP22 overexpression inhibits NSC differentiation into neurons. Interestingly, our data showed that USP22 promotes the proliferation but inhibits the differentiation of NSCs in the dentate gyrus (DG)of the hippocampus soon after TBI. The Morris water maze (MWM) test was adopted to evaluate neurological function, which confirmed that USP22 could improve the learning and memory capacity that was already compromised following TBI. Overall, this study uncovers a potentially novel regulatory role of USP22 in the proliferation and differentiation ability of NSCs, contributing to the hippocampus-dependent cognitive function of TBI mice and may be a novel target for future therapeutic approaches.
Sometimes a somatic cell undergoes an alteration of its genome leading to loss of heterozygosity (LOH). This phenomenon occurs in normal human tissues, pathological disorders, and cancers. Although previous studies in yeast have provided substantial insight into different mechanisms of LOH, mechanistic details are lacking in higher eukaryotes. Here we investigated the mechanisms giving rise to LOH, bridging the gap between unicellular yeast and higher eukaryotes using an in vivo stem cell model system in Drosophila. Our previous studies have shown that LOH arises frequently in Drosophila intestinal stem cells, and that spontaneous neoplasia arise due to LOH of tumour suppressor genes (Siudeja, 2015). Though whole-genome sequencing of somatic LOH events and profiling copy number changes and changes in heterozygosity of single-nucleotide polymorphisms, we demonstrated that LOH arises through mitotic recombination. Consistent with this, we found Rad51 to be implicated in LOH. Fine mapping of recombination sites did not reveal mutational pile-ups that commonly arise with a break-induced replication mechanism and instead showed clear examples of chromosomes resulting from cross-over resulting from double-Holliday junction-based repair. The mapped recombination regions also provided insight into potential genomic sequence features that may promote mitotic recombination, including an association with the repeated region of the Histone Locus Cluster and regions previously mapped to form R loops. We further explored how environmental factors can influence this process and demonstrate that infection with the enteric pathogenic bacteria, Ecc15, increased LOH frequency. This study provides a better mechanistic understanding of how mitotic recombination arises in stem cells in vivo, and identifies intrinsic and extrinsic factors that can drive LOH, thus providing important insight into cancer initiation and potential preventative and therapeutic strategies.
The ability to generate new hippocampal neurons throughout adulthood and successfully integrate them into existing neural networks is critical to cognitive function, while disordered regulation of this process results in neurodegenerative or psychiatric disease. Consequently, identifying the molecular mechanisms promoting homeostatic hippocampal neurogenesis in adults is essential to understanding the etiologies of these disorders and developing therapeutic interventions. For example, recent evidence identifies a strong association between metabolic function and adult hippocampal neurogenesis. Hippocampal neural stem cell (NSC) fate dynamically fluctuates with changes in substrate availability and energy status (AMP/ATP and NAD⁺/NADH ratios). Furthermore, many metabolic hormones, such as insulin, insulin-like growth factors, and leptin exhibit dual functions also modulating hippocampal neurogenesis and neuron survivability. These diverse metabolic inputs to NSC’s from various tissues seemingly suggest the existence of a system in which energy status can finely modulate hippocampal neurogenesis. Supporting this hypothesis, interventions promoting energy balance, such as caloric restriction, intermittent fasting, and exercise, have shown encouraging potential enhancing hippocampal neurogenesis and cognitive function. Overall, there is a clear relationship between whole body energy status, adult hippocampal neurogenesis, and neuron survival; however, the molecular mechanisms underlying this phenomenon are multifaceted. Thus, the aim of this review is to analyze the literature investigating energy status-mediated regulation of adult neurogenesis in the hippocampus, highlight the neurocircuitry and intracellular signaling involved, and propose impactful future directions in the field.
Aging is a significant risk factor for cognitive decline associated with neurodegenerative diseases, which makes understanding what promotes ‘healthy brain aging’ very important. Studies suggest that caloric restriction (CR) is a non-genetic intervention that reliably extends life- and healthspan. Here, we review the CR literature related to both the subject of aging and alterations in cell cycle machinery, especially surrounding the regulation of the E2F/DP1 complex, to elucidate the cellular protection mechanisms in the brain induced via dietary applications. The alterations extending lifespan via CR appear to exert their effects by promoting survival of individual cells, downregulating cell proliferation, and inducing stem cell quiescence, which results in keeping the stem cell reserve for extreme needs. This survival instinct of cells is believed to cause some molecular adaptations for their maintenance of the system. Avoiding energy waste of proliferation machinery promotes the long term survival of the individual cells and this is due to adaptations to the limited nutrient supply in the environment. Such a protective mechanism induced by diet could be promoted via the downregulation of crucial cell cycle-related transcription activators. This review article aims to bring attention to the importance of molecular adaptations induced by diet that promote healthy brain aging. It will provide insights into alternative targets for new treatments or neuroprotective approaches against neurodegenerative pathophysiologies.
Transmembrane protein 166 (TMEM166) is a lysosomal/endoplasmic reticulum (ER)-associated protein found in different species where it functions as a regulator of programmed cell death through autophagy and apoptosis. It is expressed in a variety of normal tissues and organs, and it is involved in a wide variety of physiological and pathological processes, including cancers, infection, autoimmune diseases, and neurodegenerative diseases. Previous studies indicated that TMEM166 is associated with autophagosomal membrane development. TMEM166 can cause lysosomal membrane permeabilization (LMP) leading to the release of proteolytic enzymes, e.g., cathepsins, that may cause potential mitochondrial membrane damage, which triggers several autophagic and apoptotic events. A low level of TMEM166 expression is also found in tumors, while high level of TMEM166 is found in brain ischemia. In addition, loss of TMEM166 leads to impaired NSC selfrenewal and differentiation along with a decrease in autophagy. These findings offer a comprehensive understanding of the pathways involved in the role of TMEM166 in programmed cell death and treatment of various diseases.
Inborn errors of metabolism (IEMs) occur with high incidence in human populations. Especially prevalent among these are inborn deficiencies in fatty acid β-oxidation (FAO), which are clinically associated with developmental neuropsychiatric disorders, including autism. We now report that neural stem cell (NSC)-autonomous insufficiencies in the activity of TMLHE (an autism risk factor that supports long-chain FAO by catalyzing carnitine biosynthesis), of CPT1A (an enzyme required for long-chain FAO transport into mitochondria), or of fatty acid mobilization from lipid droplets reduced NSC pools in the mouse embryonic neocortex. Lineage tracing experiments demonstrated that reduced flux through the FAO pathway potentiated NSC symmetric differentiating divisions at the expense of self-renewing stem cell division modes. The collective data reveal a key role for FAO in controlling NSC-to-IPC transition in the mammalian embryonic brain and suggest NSC self renewal as a cellular mechanism underlying the association between IEMs and autism.
Adult neurogenesis plays increasingly recognized roles in brain homeostasis and repair and is profoundly affected by energy balance and nutrients. We found that the expression of Hes-1 (hairy and enhancer of split 1) is modulated in neural stem and progenitor cells (NSCs) by extracellular glucose through the coordinated action of CREB (cyclic AMP responsive element binding protein) and Sirt-1 (Sirtuin 1), two cellular nutrient sensors. Excess glucose reduced CREB-activated Hes-1 expression and results in impaired cell proliferation. CREB-deficient NSCs expanded poorly in vitro and did not respond to glucose availability. Elevated glucose also promoted Sirt-1-dependent repression of the Hes-1 promoter. Conversely, in low glucose, CREB replaced Sirt-1 on the chromatin associated with the Hes-1 promoter enhancing Hes-1 expression and cell proliferation. Thus, the glucose-regulated antagonism between CREB and Sirt-1 for Hes-1 transcription participates in the metabolic regulation of neurogenesis.
Prolonged fasting (PF) promotes stress resistance, but its effects on longevity are poorly understood. We show that alternating PF and nutrient-rich medium extended yeast lifespan independently of established pro-longevity genes. In mice, 4 days of a diet that mimics fasting (FMD), developed to minimize the burden of PF, decreased the size of multiple organs/systems, an effect followed upon re-feeding by an elevated number of progenitor and stem cells and regeneration. Bi-monthly FMD cycles started at middle age extended longevity, lowered visceral fat, reduced cancer incidence and skin lesions, rejuvenated the immune system, and retarded bone mineral density loss. In old mice, FMD cycles promoted hippocampal neurogenesis, lowered IGF-1 levels and PKA activity, elevated NeuroD1, and improved cognitive performance. In a pilot clinical trial, three FMD cycles decreased risk factors/biomarkers for aging, diabetes, cardiovascular disease, and cancer without major adverse effects, providing support for the use of FMDs to promote healthspan.
Downregulation of insulin-like growth factor (IGF) pathways prolongs lifespan in various species, including mammals. Still, the cellular mechanisms by which IGF signaling controls the aging trajectory of individual organs are largely unknown. Here, we asked whether suppression of IGF-I receptor (IGF-1R) in adult stem cells preserves long-term cell replacement, and whether this may prevent age-related functional decline in a regenerating tissue. Using neurogenesis as a paradigm, we showed that conditional knockout of IGF-1R specifically in adult neural stem cells (NSC) maintained youthful characteristics of olfactory bulb neurogenesis within an aging brain. We found that blocking IGF-I signaling in neural precursors increased cumulative neuroblast production and enhanced neuronal integration into the olfactory bulb. This in turn resulted in neuro-anatomical changes that improved olfactory function. Interestingly, mutants also displayed long-term alterations in energy metabolism, possibly related to IGF-1R deletion in NSCs throughout lifespan. We explored Akt and ERK signaling cascades and revealed differential regulation downstream of IGF-1R, with Akt phosphorylation preferentially decreased in IGF-1R(-/-) NSCs within the niche, and ERK pathway downregulated in differentiated neurons of the OB. These challenging experimental results were sustained by data from mathematical modeling, predicting that diminished stimulation of growth is indeed optimal for tissue aging. Thus, inhibiting growth and longevity gene IGF-1R in adult NSCs induced a gain-of-function phenotype during aging, marked by optimized management of cell renewal, and enhanced olfactory sensory function.
© 2015 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.
Neural stem cells (NSCs) critical for the continued production of new neurons and glia are sequestered in distinct areas of the brain called stem cell niches. Until recently, only two forebrain sites, the subventricular zone (SVZ) of the anterolateral ventricle and the subgranular zone (SGZ) of the hippocampus, have been recognized adult stem cell niches (Alvarez-Buylla and Lim, 2004; Doetsch et al., 1999a, 1999b; Doetsch, 2003a, 2003b; Lie et al., 2004; Ming and Song, 2005). Nonetheless, the last decade has been witness to a growing literature suggesting that in fact the adult brain contains stem cell niches along the entire extent of the ventricular system. These niches are capable of widespread neurogenesis and gliogenesis, particularly after injury (Barnabé-Heider et al., 2010; Carlén et al., 2009; Decimo et al., 2012; Lin et al., 2015; Lindvall and Kokaia, 2008; Robins et al., 2013) or other inductive stimuli (Bennett et al., 2009; Cunningham et al., 2012; Decimo et al., 2011; Kokoeva et al., 2007, 2005; Lee et al., 2012; Migaud et al., 2010; Pencea et al., 2001b; Sanin et al., 2013; Suh et al., 2007; Sundholm-Peters et al., 2004; Xu et al., 2005; Zhang et al., 2007). This review focuses on the role of these novel and classic brain niches in maintaining adult neurogenesis and gliogenesis in response to normal physiological and injury-related pathological cues.
Copyright © 2015. Published by Elsevier B.V.
Neural activity is tightly coupled to energy consumption, particularly sugars such as glucose. Yet we find that, unlike mature neurons and astrocytes, neural stem/progenitor cells (NSPCs) do not require glucose to sustain aerobic respiration. NSPCs within the adult subventricular zone express enzymes required for fatty acid oxidation and show sustained increases in oxygen consumption upon treatment with a polyunsaturated fatty acid. NSPCs also demonstrate sustained decreases in oxygen consumption upon treatment with etomoxir, an inhibitor of fatty acid oxidation. In addition, etomoxir decreases the proliferation of subventricular zone NSPCs without affecting cellular survival. Finally, higher levels of neurogenesis can be achieved in aged mice by ectopically expressing PGC1a, a factor that increases cellular aerobic capacity by promoting mitochondrial biogenesis and metabolic gene transcription. Regulation of metabolic fuel availability could prove a powerful tool in promoting or limiting cellular proliferation in the central nervous system. This article is protected by copyright. All rights reserved.
© 2015 AlphaMed Press.
The adult hypothalamus regulates many physiological functions and homeostatic loops, including growth, feeding and reproduction. In mammals, the hypothalamus derives from the ventral diencephalon where two distinct ventricular proliferative zones have been described. Although a set of transcription factors regulating the hypothalamic development has been identified, the exact molecular mechanisms that drive the differentiation of hypothalamic neural precursor cells (NPCs) toward specific neuroendocrine neuronal subtypes is yet not fully disclosed. Neurogenesis has been also reported in the adult hypothalamus at the level of specific niches located in the ventrolateral region of ventricle wall, where NPCs have been identified as radial glia-like tanycytes. Here we review the molecular and cellular systems proposed to support the neurogenic potential of developing and adult hypothalamic NPCs. We also report new insights on the mechanisms by which adult hypothalamic neurogenesis modulates key functions of this brain region. Finally, we discuss how environmental factors may modulate the adult hypothalamic neurogenic cascade.
The balance between self-renewal and differentiation of adult neural stem cells (aNSCs) is essential for the maintenance of the aNSC reservoir and the continuous supply of new neurons, but how this balance is fine-tuned in the adult brain is not fully understood. Here, we investigate the role of SIRT1, an important metabolic sensor and epigenetic repressor, in regulating adult hippocampal neurogenesis in mice. We found that there was an increase in SIRT1 expression during aNSC differentiation. In Sirt1 knockout (KO) mice, as well as in brain-specific and inducible stem cell-specific conditional KO mice, the proliferation and self-renewal rates of aNSCs in vivo were elevated. Proliferation and self-renewal rates of aNSCs and adult neural progenitor cells (aNPCs) were also elevated in neurospheres derived from Sirt1 KO mice and were suppressed by the SIRT1 agonist resveratrol in neurospheres from wild-type mice. In cultured neurospheres, 2-deoxy-D-glucose-induced metabolic stress suppressed aNSC/aNPC proliferation, and this effect was mediated in part by elevating SIRT1 activity. Microarray and biochemical analysis of neurospheres suggested an inhibitory effect of SIRT1 on Notch signaling in aNSCs/aNPCs. Inhibition of Notch signaling by a γ-secretase inhibitor also largely abolished the increased aNSC/aNPC proliferation caused by Sirt1 deletion. Together, these findings indicate that SIRT1 is an important regulator of aNSC/aNPC self-renewal and a potential mediator of the effect of metabolic changes.
Proliferation of neural stem/progenitor cells (NSPCs) in the adult brain is tightly controlled to prevent exhaustion and to ensure proper neurogenesis. Several extrinsic stimuli affect NSPC regulation. However, the lack of unique markers led to controversial results regarding the in vivo behavior of NSPCs to different stimuli. We recently identified SPOT14, which controls NSPC proliferation through regulation of de novo lipogenesis, selectively in low-proliferating NSPCs. Whether SPOT14-expressing (SPOT14+) NSPCs react in vivo to neurogenic regulators is not known. We show that aging is accompanied by a marked disappearance of SPOT14+ NSPCs, whereas running, a positive neurogenic stimulus, increases proliferation of SPOT14+ NSPCs. Furthermore, transient depletion of highly proliferative cells recruits SPOT14+ NSPCs into the proliferative pool. Additionally, we have established endogenous SPOT14 protein staining, reflecting transgenic SPOT14-GFP expression. Thus, our data identify SPOT14 as a potent marker for adult NSPCs that react dynamically to positive and negative neurogenic regulators.
Neural stem/progenitor cells (NSCs) in the hippocampus produce new neurons throughout adult life. NSCs are maintained in a state of reversible quiescence and the failure to maintain the quiescent state can result in the premature depletion of the stem cell pool. The epigenetic mechanisms that maintain this quiescent state have not been identified. Using an inducible knockout mouse model, we show that the chromatin remodelling factor chromodomain-helicase-DNA-binding protein 7 (CHD7) is essential for maintaining NSC quiescence. CHD7 inactivation in adult NSCs results in a loss of stem cell quiescence in the hippocampus, a transient increase in cell divisions, followed by a significant decline in neurogenesis. This loss of NSC quiescence is associated with the premature loss of NSCs in middle-aged mice. We find that CHD7 represses the transcription of several positive regulators of cell cycle progression and is required for full induction of the Notch target gene Hes5 in quiescent NSCs. These findings directly link CHD7 to pathways involved in NSC quiescence and identify the first chromatin-remodelling factor with a role in NSC quiescence and maintenance. As CHD7 haplo-insufficiency is associated with a range of cognitive disabilities in CHARGE syndrome, our observations may have implications for understanding the basis of these deficits. Stem Cells 2014
In this study, we assessed the importance of insulin-like growth factor (IGF) and epidermal growth factor (EGF) receptor co-signaling for rat neural precursor (NP) cell proliferation and self-renewal in the context of a developmental brain injury that is associated with cerebral palsy. Consistent with previous studies, we found that there is an increase in the in vitro growth of subventricular zone NPs isolated acutely after cerebral hypoxia–ischemia; however, when cultured in medium that is insufficient to stimulate the IGF type 1 receptor, neurosphere formation and the proliferative capacity of those NPs was severely curtailed. This reduced growth capacity could not be attributed simply to failure to survive. The growth and self-renewal of the NPs could be restored by addition of both IGF-I and IGF-II. Since the size of the neurosphere is predominantly due to cell proliferation we hypothesized that the IGFs were regulating progression through the cell cycle. Analyses of cell cycle progression revealed that IGF-1R activation together with EGFR co-signaling decreased the percentage of cells in G1 and enhanced cell progression into S and G2. This was accompanied by increases in expression of cyclin D1, phosphorylated histone 3, and phosphorylated Rb. Based on these data, we conclude that coordinate signaling between the EGF receptor and the IGF type 1 receptor is necessary for the normal proliferation of NPs as well as for their reactive expansion after injury. These data indicate that manipulations that maintain or amplify IGF signaling in the brain during recovery from developmental brain injuries will enhance the production of new brain cells to improve neurological function in children who are at risk for developing cerebral palsy.
A unique property of many adult stem cells is their ability to exist in a non-cycling, quiescent state. Although quiescence serves an essential role in preserving stem cell function until the stem cell is needed in tissue homeostasis or repair, defects in quiescence can lead to an impairment in tissue function. The extent to which stem cells can regulate quiescence is unknown. Here we show that the stem cell quiescent state is composed of two distinct functional phases, G0 and an 'alert' phase we term GAlert. Stem cells actively and reversibly transition between these phases in response to injury-induced systemic signals. Using genetic mouse models specific to muscle stem cells (or satellite cells), we show that mTORC1 activity is necessary and sufficient for the transition of satellite cells from G0 into GAlert and that signalling through the HGF receptor cMet is also necessary. We also identify G0-to-GAlert transitions in several populations of quiescent stem cells. Quiescent stem cells that transition into GAlert possess enhanced tissue regenerative function. We propose that the transition of quiescent stem cells into GAlert functions as an 'alerting' mechanism, an adaptive response that positions stem cells to respond rapidly under conditions of injury and stress, priming them for cell cycle entry.
Mammalian target of rapamycin (mTOR) has been implicated in human neurological diseases such as tuberous sclerosis complex (TSC), neurodegeneration, and autism. However, little is known about when and how mTOR is involved in the pathogenesis of these diseases, due to a lack of animal models that directly increase mTOR activity. Here, we generated transgenic mice expressing a gain-of-function mutant of mTOR in the forebrain in a temporally controlled manner. Selective activation of mTORC1 in embryonic stages induced cortical atrophy caused by prominent apoptosis of neuronal progenitors, associated with upregulation of HIF-1α. In striking contrast, activation of the mTORC1 pathway in adulthood resulted in cortical hypertrophy with fatal epileptic seizures, recapitulating human TSC. Activated mTORC1 in the adult cortex also promoted rapid accumulation of cytoplasmic inclusions and activation of microglial cells, indicative of progressive neurodegeneration. Our findings demonstrate that mTORC1 plays different roles in developmental and adult stages and contributes to human neurological diseases.
Throughout life, new neurons are continuously added to the dentate gyrus. As this continuous addition remodels hippocampal
circuits, computational models predict that neurogenesis leads to degradation or forgetting of established memories. Consistent
with this, increasing neurogenesis after the formation of a memory was sufficient to induce forgetting in adult mice. By contrast,
during infancy, when hippocampal neurogenesis levels are high and freshly generated memories tend to be rapidly forgotten
(infantile amnesia), decreasing neurogenesis after memory formation mitigated forgetting. In precocial species, including
guinea pigs and degus, most granule cells are generated prenatally. Consistent with reduced levels of postnatal hippocampal
neurogenesis, infant guinea pigs and degus did not exhibit forgetting. However, increasing neurogenesis after memory formation
induced infantile amnesia in these species.
Skeletal muscle stem cells, or "satellite cells" (SCs), are required for the regeneration of damaged muscle tissue. Although SCs self-renew during regeneration, the mechanisms that govern SC re-entry into quiescence remain elusive. We show that FOXO3, a member of the forkhead family of transcription factors, is expressed in quiescent SCs (QSCs). Conditional deletion of Foxo3 in QSCs impairs self-renewal and increases the propensity of SCs to adopt a differentiated fate. Transcriptional analysis of SCs lacking FOXO3 revealed a downregulation of Notch signaling, a key regulator of SC quiescence. Conversely, overexpression of Notch intracellular domain (NICD) rescued the self-renewal deficit of FOXO3-deficient SCs. We show that FOXO3 regulates NOTCH1 and NOTCH3 receptor expression and that decreasing expression of NOTCH1 and NOTCH3 receptors phenocopies the effect of FOXO3 deficiency in SCs. We demonstrate that FOXO3, perhaps by activating Notch signaling, promotes the quiescent state during SC self-renewal in adult muscle regeneration.
Adult neurogenesis is thought to be crucial for preserving cognitive functions, which is tightly controlled by various epigenetic regulators. As the methyltransferase of histone H3K27, the role of Ezh2 in neurogenesis of adult mice and its mechanism of action are largely unknown. Here, we show that Ezh2 is expressed in actively dividing neural stem cells (NSCs)/progenitor cells as well as mature neurons, but not in quiescent NSCs in the subgranular zone. The deletion of Ezh2 in NSCs/progenitor cells results in a reduction in progenitor cell proliferation. Furthermore, we found that Ezh2 regulates progenitor cell proliferation by suppressing Pten expression and promoting the activation of Akt-mTOR. Moreover, the loss of Ezh2 in progenitor cells leads to a decrease in the number of neurons, which was observed by long-term tracing. Strikingly, conditional knockout of Ezh2 ultimately results in impairments in spatial learning and memory, contextual fear memory, and pattern separation. Our findings demonstrate the essential role of Ezh2 in the proliferation of progenitor cells, thus providing insight into the molecular mechanisms of adult neurogenesis in preserving cognitive functions.
The subgranular zone (SGZ) of the adult hippocampus contains a pool of quiescent neural progenitor cells (QNPs) that are capable of entering the cell cycle and producing newborn neurons. The mechanisms that control the timing and extent of adult neurogenesis are not well understood. Here, we show that QNPs of the adult SGZ express molecular-clock components and proliferate in a rhythmic fashion. The clock proteins PERIOD2 and BMAL1 are critical for proper control of neurogenesis. The absence of PERIOD2 abolishes the gating of cell-cycle entrance of QNPs, whereas genetic ablation of bmal1 results in constitutively high levels of proliferation and delayed cell-cycle exit. We use mathematical model simulations to show that these observations may arise from clock-driven expression of a cell-cycle inhibitor that targets the cyclin D/Cdk4-6 complex. Our findings may have broad implications for the circadian clock in timing cell-cycle events of other stem cell populations throughout the body.
Stem cells exert precise regulation to maintain a balance of self-renewal and differentiation programs to sustain tissue homeostasis throughout the life of an organism. Recent evidence suggests that this regulation is modulated, in part, via metabolic changes and modifications of nutrient-sensing pathways such as mTOR and AMPK. It is becoming increasingly clear that stem cells inhibit oxidative phosphorylation in favor of aerobic glycolysis for energy production. Recent progress has detailed the molecular mechanisms of this metabolic phenotype and has offered insight into new metabolic pathways that may be involved in stem cell homeostasis.
Metabolism is influenced by age, food intake, and conditions such as diabetes and obesity. How do physiological or pathological metabolic changes influence stem cells, which are crucial for tissue homeostasis? This Commentary reviews recent evidence that stem cells have different metabolic demands than differentiated cells, and that the molecular mechanisms that control stem cell self-renewal and differentiation are functionally connected to the metabolic state of the cell and the surrounding stem cell niche. Furthermore, we present how energy-sensing signaling molecules and metabolism regulators are implicated in the regulation of stem cell self-renewal and differentiation. Finally, we discuss the emerging literature on the metabolism of induced pluripotent stem cells and how manipulating metabolic pathways might aid cellular reprogramming. Determining how energy metabolism regulates stem cell fate should shed light on the decline in tissue regeneration that occurs during aging and facilitate the development of therapies for degenerative or metabolic diseases.
Mechanisms controlling the proliferative activity of neural stem and progenitor cells (NSPCs) have a pivotal role to ensure life-long neurogenesis in the mammalian brain. How metabolic programs are coupled with NSPC activity remains unknown. Here we show that fatty acid synthase (Fasn), the key enzyme of de novo lipogenesis, is highly active in adult NSPCs and that conditional deletion of Fasn in mouse NSPCs impairs adult neurogenesis. The rate of de novo lipid synthesis and subsequent proliferation of NSPCs is regulated by Spot14, a gene previously implicated in lipid metabolism, that we found to be selectively expressed in low proliferating adult NSPCs. Spot14 reduces the availability of malonyl-CoA, which is an essential substrate for Fasn to fuel lipogenesis. Thus, we identify here a functional coupling between the regulation of lipid metabolism and adult NSPC proliferation.
Adult forebrain neurogenesis is dynamically regulated. Multiple families of niche-derived cues have been implicated in this regulation, but the precise roles of key intracellular signaling pathways remain vaguely defined. Here, we show that mammalian target of rapamycin (mTOR) signaling is pivotal in determining proliferation versus quiescence in the adult forebrain neural stem cell (NSC) niche. Within this niche, mTOR complex-1 (mTORC1) activation displays stage specificity, occurring in transiently amplifying (TA) progenitor cells but not in GFAP+ stem cells. Inhibiting mTORC1 depletes the TA progenitor pool in vivo and suppresses epidermal growth factor (EGF)-induced proliferation within neurosphere cultures. Interestingly, mTORC1 inhibition induces a quiescence-like phenotype that is reversible. Likewise, mTORC1 activity and progenitor proliferation decline within the quiescent NSC niche of the aging brain, while EGF administration reactivates the quiescent niche in an mTORC1-dependent manner. These findings establish fundamental links between mTOR signaling, proliferation, and aging-associated quiescence in the adult forebrain NSC niche.
Neurogenesis in the adult hippocampus involves activation of quiescent neural stem cells (NSCs) to yield transiently amplifying NSCs, progenitors, and, ultimately, neurons that affect learning and memory. This process is tightly controlled by microenvironmental cues, although a few endogenous factors are known to regulate neuronal differentiation. Astrocytes have been implicated, but their role in juxtacrine (that is, cell-cell contact dependent) signaling in NSC niches has not been investigated. We found that ephrin-B2 presented from rodent hippocampal astrocytes regulated neurogenesis in vivo. Furthermore, clonal analysis in NSC fate-mapping studies revealed a previously unknown role for ephrin-B2 in instructing neuronal differentiation. In addition, ephrin-B2 signaling, transduced by EphB4 receptors on NSCs, activated β-catenin in vitro and in vivo independently of Wnt signaling and upregulated proneural transcription factors. Ephrin-B2(+) astrocytes therefore promote neuronal differentiation of adult NSCs through juxtacrine signaling, findings that advance our understanding of adult neurogenesis and may have future regenerative medicine implications.
Adult neural stem cells (NSCs) are known to exist in a few regions of the brain; however, the entity and physiological/disease relevance of adult hypothalamic NSCs (htNSCs) remain unclear. This work shows that adult htNSCs are multipotent and predominantly present in the mediobasal hypothalamus of adult mice. Chronic high-fat-diet feeding led to not only depletion but also neurogenic impairment of htNSCs associated with IKKβ/NF-κB activation. In vitro htNSC models demonstrated that their survival and neurogenesis markedly decreased on IKKβ/NF-κB activation but increased on IKKβ/NF-κB inhibition, mechanistically mediated by IKKβ/NF-κB-controlled apoptosis and Notch signalling. Mouse studies revealed that htNSC-specific IKKβ/NF-κB activation led to depletion and impaired neuronal differentiation of htNSCs, and ultimately the development of obesity and pre-diabetes. In conclusion, adult htNSCs are important for the central regulation of metabolic physiology, and IKKβ/NF-κB-mediated impairment of adult htNSCs is a critical neurodegenerative mechanism for obesity and related diabetes.
Stem-cell function is an exquisitely regulated process. Thus far, the contribution of metabolic cues to stem-cell function has not been well understood. Here we identify a previously unknown promyelocytic leukemia (PML)-peroxisome proliferator-activated receptor δ (PPAR-δ)-fatty-acid oxidation (FAO) pathway for the maintenance of hematopoietic stem cells (HSCs). We have found that loss of PPAR-δ or inhibition of mitochondrial FAO induces loss of HSC maintenance, whereas treatment with PPAR-δ agonists improved HSC maintenance. PML exerts its essential role in HSC maintenance through regulation of PPAR signaling and FAO. Mechanistically, the PML-PPAR-δ-FAO pathway controls the asymmetric division of HSCs. Deletion of Ppard or Pml as well as inhibition of FAO results in the symmetric commitment of HSC daughter cells, whereas PPAR-δ activation increased asymmetric cell division. Thus, our findings identify a metabolic switch for the control of HSC cell fate with potential therapeutic implications.
How adult tissue stem and niche cells respond to the nutritional state of an organism is not well understood. Here we find that Paneth cells, a key constituent of the mammalian intestinal stem-cell (ISC) niche, augment stem-cell function in response to calorie restriction. Calorie restriction acts by reducing mechanistic target of rapamycin complex 1 (mTORC1) signalling in Paneth cells, and the ISC-enhancing effects of calorie restriction can be mimicked by rapamycin. Calorie intake regulates mTORC1 in Paneth cells, but not ISCs, and forced activation of mTORC1 in Paneth cells during calorie restriction abolishes the ISC-augmenting effects of the niche. Finally, increased expression of bone stromal antigen 1 (Bst1) in Paneth cells—an ectoenzyme that produces the paracrine factor cyclic ADP ribose—mediates the effects of calorie restriction and rapamycin on ISC function. Our findings establish that mTORC1 non-cell-autonomously regulates stem-cell self-renewal, and highlight a significant role of the mammalian intestinal niche in coupling stem-cell function to organismal physiology.
In the CNS, the hypothalamic arcuate nucleus (ARN) energy-balance circuit plays a key role in regulating body weight. Recent studies have shown that neurogenesis occurs in the adult hypothalamus, revealing that the ARN energy-balance circuit is more plastic than originally believed. Changes in diet result in altered gene expression and neuronal activity in the ARN, some of which may reflect hypothalamic plasticity. To explore this possibility, we examined the turnover of hypothalamic neurons in mice with obesity secondary to either high-fat diet (HFD) consumption or leptin deficiency. We found substantial turnover of neurons in the ARN that resulted in ongoing cellular remodeling. Feeding mice HFD suppressed neurogenesis, as demonstrated by the observation that these mice both generated fewer new neurons and retained more old neurons. This suppression of neuronal turnover was associated with increased apoptosis of newborn neurons. Leptin-deficient mice also generated fewer new neurons, an observation that was explained in part by a loss of hypothalamic neural stem cells. These data demonstrate that there is substantial postnatal turnover of the arcuate neuronal circuitry in the mouse and reveal the unexpected capacity of diet and leptin deficiency to inhibit this neuronal remodeling. This insight has important implications for our understanding of nutritional regulation of energy balance and brain function.
Calorie restriction delays brain senescence and prevents neurodegeneration, but critical regulators of these beneficial responses other than the NAD(+)-dependent histone deacetylase Sirtuin-1 (Sirt-1) are unknown. We report that effects of calorie restriction on neuronal plasticity, memory and social behavior are abolished in mice lacking cAMP responsive-element binding (CREB)-1 in the forebrain. Moreover, CREB deficiency drastically reduces the expression of Sirt-1 and the induction of genes relevant to neuronal metabolism and survival in the cortex and hippocampus of dietary-restricted animals. Biochemical studies reveal a complex interplay between CREB and Sirt-1: CREB directly regulates the transcription of the sirtuin in neuronal cells by binding to Sirt-1 chromatin; Sirt-1, in turn, is recruited by CREB to DNA and promotes CREB-dependent expression of target gene peroxisome proliferator-activated receptor-γ coactivator-1α and neuronal NO Synthase. Accordingly, expression of these CREB targets is markedly reduced in the brain of Sirt KO mice that are, like CREB-deficient mice, poorly responsive to calorie restriction. Thus, the above circuitry, modulated by nutrient availability, links energy metabolism with neurotrophin signaling, participates in brain adaptation to nutrient restriction, and is potentially relevant to accelerated brain aging by overnutrition and diabetes.
In the central nervous system, ageing results in a precipitous decline in adult neural stem/progenitor cells and neurogenesis, with concomitant impairments in cognitive functions. Interestingly, such impairments can be ameliorated through systemic perturbations such as exercise. Here, using heterochronic parabiosis we show that blood-borne factors present in the systemic milieu can inhibit or promote adult neurogenesis in an age-dependent fashion in mice. Accordingly, exposing a young mouse to an old systemic environment or to plasma from old mice decreased synaptic plasticity, and impaired contextual fear conditioning and spatial learning and memory. We identify chemokines--including CCL11 (also known as eotaxin)--the plasma levels of which correlate with reduced neurogenesis in heterochronic parabionts and aged mice, and the levels of which are increased in the plasma and cerebrospinal fluid of healthy ageing humans. Lastly, increasing peripheral CCL11 chemokine levels in vivo in young mice decreased adult neurogenesis and impaired learning and memory. Together our data indicate that the decline in neurogenesis and cognitive impairments observed during ageing can be in part attributed to changes in blood-borne factors.
It has been hypothesized that a signaling pathway for regulating aging and longevity may be involved in stem cell functions. To address the hypothesis we investigate roles of molecules that regulate aging on self-renewal capacity of HSC.
Ataxia telangiectasia (A-T) is an autosomal recessive disorder caused by mutational inactivation of the ATM. ATM has a central role in maintenance of genomic stability via regulating cell cycle checkpoint in response to DNA damage, stability of telomere and oxidative stress. A-T patients display variety of sympotoms including high incidence of lymphoma and premature aging. In this study we investigated the effects of ATM deficiency on the hematopoietic system.
ATM−/− mice have normal numbers of peripheral blood cells and colony-forming cells in the bone marrow (BM) at the age of 8 weeks. A frequency of KSL in the ATM−/− BM was similar to that of wild-type mice. However, the number of colony-forming cells derived from ATM−/− KSL cells after 6 weeks co-culture of stromal cells was significantly decreased. To directly assess a repopulating ability of the HSC in vivo, we performed a competitive reconstitution assay with congenic mice. Short-term (4-weeks) repopulation was not affected. However, there were dramatically fewer hematopoietic cells derived from ATM−/− BM at 16 weeks post-transplant, indicating that ATM has an essential role in the self-renewal of adult HSCs, but is not required for the differentiation or proliferation of hematopoietic progenitor cells.
We next evaluated the effects of ATM deficiency on hematopoiesis in older mice. All ATM−/− mice older than 20 weeks exhibited a progressive pancytopenia with hypocellularity in bone marrow. The numbers of myeloid and erythroid precursors among ATM−/− BM MNCs were markedly decreased, KSL cells had disappeared, and co-culture on stromal cells showed that ATM−/− cells were no longer able to form any colonies after 2 weeks of culture. Taken together, our data indicate that chronic ATM deficiency in vivo results in progressive multi-lineage BM failure due to defective maintenance of the adult HSC pool.
ATM is involved in oxidative defense, and the loss of ATM results in oxidative damage in several tissues. To elucidate the mechanism underlying the regulation of the HSC pool by ATM, we next evaluated ROS generation in HSC, and were able to demonstrate that the intracellular concentration of radical oxygen was higher in KSL cells from ATM−/− mice than from WT animals. Two members of CDK inhibitors, p16 and p19, were highly elevated in ATM−/− KSL cells after 2 days in vitro incubation with cytokines. Treatment with the permeant thiol N-acetylcysteine (NAC) abrogated the upregulation of p16 and p19 expression and BM failure corresponding to decrease in the level of intracellular ROS.
The numbers of colonies formed from ATM−/− HSCs were restored to near-WT levels by treatment with either NAC or catalase in long term culture. Furthermore we found that NAC treatment of ATM−/− mice dramatically restored the repopulation capacity comparable to that of the WT. We conclude that self-renewal capacity of HSCs depends on ATM-mediated inhibition of oxidative stress. Our data support a model in which master regulator molecules govern the disparate processes of stem cell self-renewal, normal aging and tumor development.
Somatic stem cells contribute to tissue ontogenesis, homeostasis, and regeneration through sequential processes. Systematic molecular analysis of stem cell behavior is challenging because classic approaches cannot resolve cellular heterogeneity or capture developmental dynamics. Here we provide a comprehensive resource of single-cell transcriptomes of adult hippocampal quiescent neural stem cells (qNSCs) and their immediate progeny. We further developed Waterfall, a bioinformatic pipeline, to statistically quantify singe-cell gene expression along a de novo reconstructed continuous developmental trajectory. Our study reveals molecular signatures of adult qNSCs, characterized by active niche signaling integration and low protein translation capacity. Our analyses further delineate molecular cascades underlying qNSC activation and neurogenesis initiation, exemplified by decreased extrinsic signaling capacity, primed translational machinery, and regulatory switches in transcription factors, metabolism, and energy sources. Our study reveals the molecular continuum underlying adult neurogenesis and illustrates how Waterfall can be used for single-cell omics analyses of various continuous biological processes.
Copyright © 2015 Elsevier Inc. All rights reserved.
Hypothalamic tanycytes are specialized glial cells lining the third ventricle. They were recently identified as adult stem/progenitor cells, able to self-renew and give rise to new neurons postnatally. However, the long-term neurogenic potential of tanycytes and the pathways regulating lifelong cell replacement in the adult hypothalamus are largely unexplored. Using inducible nestin-CreERT2 for conditional mutagenesis, we performed lineage tracing of adult hypothalamic stem/progenitor cells (HySC), and demonstrated that new neurons continue to be born throughout adult life. This neurogenesis was targeted to numerous hypothalamic nuclei and produced different types of neurons in the dorsal periventricular regions. Some adult-born neurons integrated the median eminence and arcuate nucleus during aging and produced GHRH. We showed that adult hypothalamic neurogenesis was tightly controlled by insulin-like growth factors (IGF). Knockout of IGF-I receptor from HySC increased neuronal production and enhanced α-tanycyte self-renewal, preserving this stem cell-like population from age-related attrition. Our data indicate that adult hypothalamus retains the capacity of cell renewal, and thus a substantial degree of structural plasticity throughout lifespan.
Chen et al. 2008. J. Exp. Med. doi:10.1084/jem.20081297[OpenUrl][1][Abstract/FREE Full Text][2]
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Long-term survival and antitumor immunity of adoptively transferred CD8(+) T cells is dependent on their metabolic fitness, but approaches to isolate therapeutic T cells based on metabolic features are not well established. Here we utilized a lipophilic cationic dye tetramethylrhodamine methyl ester (TMRM) to identify and isolate metabolically robust T cells based on their mitochondrial membrane potential (ΔΨm). Comprehensive metabolomic and gene expression profiling demonstrated global features of improved metabolic fitness in low-ΔΨm-sorted CD8(+) T cells. Transfer of these low-ΔΨm T cells was associated with superior long-term in vivo persistence and an enhanced capacity to eradicate established tumors compared with high-ΔΨm cells. Use of ΔΨm-based sorting to enrich for cells with superior metabolic features was observed in CD8(+), CD4(+) T cell subsets, and long-term hematopoietic stem cells. This metabolism-based approach to cell selection may be broadly applicable to therapies involving the transfer of HSC or lymphocytes for the treatment of viral-associated illnesses and cancer.
To reduce the computational complexity and latency of Turbo decoding, a new decoding scheme is proposed. Firstly, the Max-Log-MAP algorithm is modified to improve performance while guarantee the calculation simplicity at the same time. Then, the parallel decoding scheme was introduced, and an improvement is made so that the two SISO decoders can work at the same time. The simulation results show that the performance of Max-Log-MAP algorithm improves 0.1~0.4 dB. Besides, the change of decoding structure doesn't bring extra iterations, while decoding latency per iteration decreases, the whole system is surely more real-time.
Lipid metabolism is fundamental for brain development and function, but its roles in normal and pathological neural stem cell (NSC) regulation remain largely unexplored. Here, we uncover a fatty acid-mediated mechanism suppressing endogenous NSC activity in Alzheimer's disease (AD). We found that postmortem AD brains and triple-transgenic Alzheimer's disease (3xTg-AD) mice accumulate neutral lipids within ependymal cells, the main support cell of the forebrain NSC niche. Mass spectrometry and microarray analyses identified these lipids as oleic acid-enriched triglycerides that originate from niche-derived rather than peripheral lipid metabolism defects. In wild-type mice, locally increasing oleic acid was sufficient to recapitulate the AD-associated ependymal triglyceride phenotype and inhibit NSC proliferation. Moreover, inhibiting the rate-limiting enzyme of oleic acid synthesis rescued proliferative defects in both adult neurogenic niches of 3xTg-AD mice. These studies support a pathogenic mechanism whereby AD-induced perturbation of niche fatty acid metabolism suppresses the homeostatic and regenerative functions of NSCs.
Copyright © 2015 Elsevier Inc. All rights reserved.
Heterogeneous pools of adult neural stem cells (NSCs) contribute to brain maintenance and regeneration after injury. The balance of NSC activation and quiescence, as well as the induction of lineage-specific transcription factors, may contribute to diversity of neuronal and glial fates. To identify molecular hallmarks governing these characteristics, we performed single-cell sequencing of an unbiased pool of adult subventricular zone NSCs. This analysis identified a discrete, dormant NSC subpopulation that already expresses distinct combinations of lineage-specific transcription factors during homeostasis. Dormant NSCs enter a primed-quiescent state before activation, which is accompanied by downregulation of glycolytic metabolism, Notch, and BMP signaling and a concomitant upregulation of lineage-specific transcription factors and protein synthesis. In response to brain ischemia, interferon gamma signaling induces dormant NSC subpopulations to enter the primed-quiescent state. This study unveils general principles underlying NSC activation and lineage priming and opens potential avenues for regenerative medicine in the brain.
Copyright © 2015 Elsevier Inc. All rights reserved.
Insulin and insulin-like growth factors (IGFs) are important regulators of growth and metabolism. In both vertebrates and invertebrates, insulin/IGFs are made available to various organs, including the brain, through two routes: the circulating systemic insulin/IGFs act on distant organs via endocrine signalling, whereas insulin/IGF ligands released by local tissues act in a paracrine or autocrine fashion. Although the mechanisms governing the secretion and action of systemic insulin/IGF have been the focus of extensive investigation, the significance of locally derived insulin/IGF has only more recently come to the fore. Local insulin/IGF signalling is particularly important for the development and homeostasis of the central nervous system, which is insulated from the systemic environment by the blood-brain barrier. Local insulin/IGF signalling from glial cells, the blood-brain barrier and the cerebrospinal fluid has emerged as a potent regulator of neurogenesis. This review will address the main sources of local insulin/IGF and how they affect neurogenesis during development. In addition, we describe how local insulin/IGF signalling couples neural stem cell proliferation with systemic energy state in Drosophila and in mammals.
Organismal diet has a profound impact on tissue homeostasis and health in mammals. Adult stem cells are a keystone of tissue homeostasis that alters tissue composition by balancing self-renewal and differentiation divisions. Because somatic stem cells may respond to shifts in organismal physiology to orchestrate tissue remodeling and some cancers are understood to arise from transformed stem cells, there is a likely possibility that organismal diet, stem cell function, and cancer initiation are interconnected. Here we will explore the emerging effects of diet on nutrient-sensing pathways active in mammalian tissue stem cells and their relevance to normal and cancerous growth.
One of the landmark events of the past 25 years in neuroscience research was the establishment of neural stem cells (NSCs) as a life-long source of neurons and glia, a concept that shattered the dogma that the nervous system lacked regenerative power. Stem cells afford the plasticity to generate, repair, and change nervous system function. Combined with reprogramming technology, human somatic cell-derived NSCs and their progeny can model neurological diseases with improved accuracy. As technology advances, we anticipate further important discoveries and novel therapies based on the knowledge and application of these powerful cells.
The adult mammalian brain contains populations of stem cells that can proliferate and then differentiate into neurons or glia.
The highest concentration of such neural progenitor cells (NPC) is located in the subventricular zone (SVZ) and these cells
can produce new olfactory bulb and cerebral cortical neurons. NPC may provide a cellular reservoir for replacement of cells
lost during normal cell turnover and after brain injury. However, neurogenesis does not compensate for neuronal loss in age-related
neurodegenerative disorders such as Alzheimer’s disease (AD), suggesting the possibility that impaired neurogenesis contributes
to the pathogenesis of such disorders. We now report that amyloid β-peptide (Aβ), a self-aggregating neurotoxic protein thought
to cause AD, can impair neurogenesis in the SVZ/cerebral cortex of adult mice and in human cortical NPC in culture. The proliferation
and migration of NPC in the SVZ of amyloid precursor protein (APP) mutant mice, and in mice receiving an intraventricular
infusion of Aβ, were greatly decreased compared to control mice. Studies of NPC neurosphere cultures derived from human embryonic
cerebral cortex showed that Aβ can suppress NPC proliferation and differentiation, and can induce apoptosis. The adverse effects
of Aβ on neurogenesis were associated with a disruption of calcium regulation in the NPC. Our data show that Aβ can impair
cortical neurogenesis, and suggest that this adverse effect of Aβ contributes to the depletion of neurons and the resulting
olfactory and cognitive deficits in AD.
When mammals fast, glucose homeostasis is achieved by triggering expression of gluconeogenic genes in response to glucagon and glucocorticoids. The pathways act synergistically to induce gluconeogenesis (glucose synthesis), although the underlying mechanism has not been determined. Here we show that mice carrying a targeted disruption of the cyclic AMP (cAMP) response element binding (CREB) protein gene, or overexpressing a dominant-negative CREB inhibitor, exhibit fasting hypoglycaemia [corrected] and reduced expression of gluconeogenic enzymes. CREB was found to induce expression of the gluconeogenic programme through the nuclear receptor coactivator PGC-1, which is shown here to be a direct target for CREB regulation in vivo. Overexpression of PGC-1 in CREB-deficient mice restored glucose homeostasis and rescued expression of gluconeogenic genes. In transient assays, PGC-1 potentiated glucocorticoid induction of the gene for phosphoenolpyruvate carboxykinase (PEPCK), the rate-limiting enzyme in gluconeogenesis. PGC-1 promotes cooperativity between cyclic AMP and glucocorticoid signalling pathways during hepatic gluconeogenesis. Fasting hyperglycaemia is strongly correlated with type II diabetes, so our results suggest that the activation of PGC-1 by CREB in liver contributes importantly to the pathogenesis of this disease.
Throughout life, neural stem cells (NSCs) in the adult hippocampus persistently generate new neurons that modify the neural circuitry. Adult NSCs constitute a relatively quiescent cell population but can be activated by extrinsic neurogenic stimuli. However, the molecular mechanism that controls such reversible quiescence and its physiological significance have remained unknown. Here, we show that the cyclin-dependent kinase inhibitor p57kip2 (p57) is required for NSC quiescence. In addition, our results suggest that reduction of p57 protein in NSCs contributes to the abrogation of NSC quiescence triggered by extrinsic neurogenic stimuli such as running. Moreover, deletion of p57 in NSCs initially resulted in increased neurogenesis in young adult and aged mice. Long-term p57 deletion, on the contrary, led to NSC exhaustion and impaired neurogenesis in aged mice. The regulation of NSC quiescence by p57 might thus have important implications for the short-term (extrinsic stimuli-dependent) and long-term (age-related) modulation of neurogenesis.
Overnutrition-induced diseases such as obesity and type 2 diabetes (T2D) involve neural dysregulation of metabolic physiology. Recently, interdisciplinary research in neuroscience and immunology has linked overnutrition to a non-classical onset of inflammation in the brain, particularly in the hypothalamus. This neuroinflammation impairs central regulatory pathways of energy balance and nutrient metabolism, and leads to obesity, diabetes, and cardiovascular complications. This review describes recent findings on the roles of overnutrition-induced hypothalamic inflammation in neurodegeneration and defective adult neurogenesis, as well as in impaired neural stem cell regeneration, and their relevance to obesity and related diseases. In addition, commonalities in terms of neuroinflammation between neurodegenerative diseases and overnutrition-induced metabolic diseases are discussed. Targeting neuroinflammation and neurodegeneration will provide promising approaches for treating obesity and other overnutrition-related diseases.
The evidence that neurogenesis occurs in the adult brain and neural stem cells (NSCs) reside in the adult central nervous system (CNS) of mammals opens new avenues and opportunities for our understanding of development and for therapy. Newly generated neuronal cells of the adult brain would contribute to the physio-pathology of the nervous system and the adult brain may be amenable to repair. The contribution of adult neurogenesis to the functioning of the nervous system remains to be elucidated and adult NSCs have yet to be brought to therapy. It is generally accepted that NSCs in the adult brain have a regenerative capacity. Yet, evidences suggest that they may also contribute to pathological developments in neurological diseases. Alzheimer's disease (AD) is a neurodegenerative disease and the hippocampus is one of the regions of the brain the most affected by the disease. AD is characterized by neurodegeneration, amyloid plaques, neurofibrillary tangles, aneuploidy and enhanced neurogenesis in the adult brain. The process of adult neurogenesis holds the potential to generate populations of cells that are aneuploid, particularly in the neurogenic regions. Aneuploid newly generated neuronal cells of the adult brain would contribute to the pathology of AD. Adult neurogenesis would not only contribute to regenerative attempts in the CNS, but also to the pathogenesis of neurological diseases and disorders.
There are many indications that neurogenesis is impaired in Parkinson's disease, which might be due to a lack of dopamine in the subventricular zone. An impairment in neurogenesis may have negative consequences for the development of new therapeutic approaches in Parkinson's disease, as neural stem cells are a potential source for endogenous repair. In this study, we examined the subventricular zone of 10 patients with Parkinson's disease and 10 age- and sex-matched controls for proliferation and neural stem cell numbers. We also included five cases with incidental Lewy body disease, which showed Parkinson's disease pathology but no clinical symptoms and thus did not receive dopaminergic treatment. We quantified the neural stem cell number and proliferative capacity in the subventricular zone of these three donor groups. We found subventricular neural stem cells in each donor, with a high variation in number. We did not observe significant differences in neural stem cell number or in proliferation between the groups. Additionally, we were able to culture neural stem cells from post-mortem brain of several patients with Parkinson's disease, confirming the presence of viable neural stem cells in these brains. We have also examined the subventricular zone of a chronic, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinson's disease mouse model, and again found no effect of dopaminergic denervation on precursor proliferation. Lastly, we investigated the proliferation capacity of two different human neural stem cell lines in response to dopamine. Both cell lines did not respond with a change in proliferation to treatment with dopamine agonists and an antagonist. In summary, the adult neural stem cell pool in the subventricular zone was not clearly affected in the human parkinsonian brain or a Parkinson's disease mouse model. Furthermore, we did not find evidence that dopamine has a direct effect on human neural stem cell proliferation in vitro. Thus, we conclude that the number of adult neural stem cells is probably not diminished in the parkinsonian brain and that dopamine depletion most likely has no effect on human neural stem cells.
Tuberous Sclerosis Complex (TSC) is a multisystem genetic disorder characterized by hamartomatous neurological lesions that exhibit abnormal cell proliferation and differentiation. Hyperactivation of mTOR pathway by mutations in either the Tsc1 or Tsc2 gene underlies TSC pathogenesis, but involvement of specific neural cell populations in the formation of TSC-associated neurological lesions remains unclear. We deleted Tsc1 in Emx1-expressing embryonic telencephalic neural stem cells (NSCs) and found that mutant mice faithfully recapitulated TSC neuropathological lesions, such as cortical lamination defects and subependymal nodules (SENs). These alterations were caused by enhanced generation of SVZ neural progeny, followed by their premature differentiation and impaired maturation during both embryonic and postnatal development. Notably, mTORC1-dependent Akt inhibition and STAT3 activation were involved in the reduced self-renewal and earlier neuronal and astroglial differentiation of mutant NSCs. Thus, finely tuned mTOR activation in embryonic NSCs may be critical to prevent development of TSC-associated brain lesions.
Newborn neurons derived from radial glia-like stem cells located in the dentate gyrus integrate into the adult hippocampal circuitry and participate in memory formation, spatial learning, pattern separation, fear conditioning, and anxiety. This process takes place throughout the life span of mammals, including humans; however, it follows a sharp declining curve. New neurons are generated abundantly during youth but very scarcely in the aged brain. The absolute number of newly generated neurons, or neurogenic output, is determined at different levels along the neurogenic cascade: the activation of quiescent stem cells; the mitotic potential of proliferating precursors; and the survival of neuronal fate-committed precursors. A continuous depletion of the hippocampal neural stem cell pool has been recently proposed as the main force underlying the age-related decline of neurogenesis, in contrast to the previous view of population of neural stem cells whose number remains constant but loses its ability to bear fruit. Nevertheless, the diminished neurogenic output may be reflecting other phenomena such as decreased mitotic capability of proliferating progenitors, decreased survival or changes in differentiation. We describe herein the most important events in determining the amount of neurogenesis in the dentate gyrus and examine the literature to understand the effects of age throughout the cascade.
Adult neurogenesis, a process of generating functional neurons from adult neural precursors, occurs throughout life in restricted brain regions in mammals. The past decade has witnessed tremendous progress in addressing questions related to almost every aspect of adult neurogenesis in the mammalian brain. Here we review major advances in our understanding of adult mammalian neurogenesis in the dentate gyrus of the hippocampus and from the subventricular zone of the lateral ventricle, the rostral migratory stream to the olfactory bulb. We highlight emerging principles that have significant implications for stem cell biology, developmental neurobiology, neural plasticity, and disease mechanisms. We also discuss remaining questions related to adult neural stem cells and their niches, underlying regulatory mechanisms, and potential functions of newborn neurons in the adult brain. Building upon the recent progress and aided by new technologies, the adult neurogenesis field is poised to leap forward in the next decade.