Systemic signals regulate ageing and rejuvenation of blood stem cell niches

Department of Stem Cell and Regenerative Biology, Harvard University, Howard Hughes Medical Institute, Harvard Stem Cell Institute, Joslin Diabetes Center, One Joslin Place, Boston, Massachusetts 02115, USA.
Nature (Impact Factor: 42.35). 10/2010; 467(7317):872. DOI: 10.1038/nature09474
Source: PubMed

ABSTRACT Ageing in multicellular organisms typically involves a progressive decline in cell replacement and repair processes, resulting in several physiological deficiencies, including inefficient muscle repair, reduced bone mass, and dysregulation of blood formation (haematopoiesis). Although defects in tissue-resident stem cells clearly contribute to these phenotypes, it is unclear to what extent they reflect stem cell intrinsic alterations or age-related changes in the stem cell supportive microenvironment, or niche. Here, using complementary in vivo and in vitro heterochronic models, we show that age-associated changes in stem cell supportive niche cells deregulate normal haematopoiesis by causing haematopoietic stem cell dysfunction. Furthermore, we find that age-dependent defects in niche cells are systemically regulated and can be reversed by exposure to a young circulation or by neutralization of the conserved longevity regulator, insulin-like growth factor-1, in the marrow microenvironment. Together, these results show a new and critical role for local and systemic factors in signalling age-related haematopoietic decline, and highlight a new model in which blood-borne factors in aged animals act through local niche cells to induce age-dependent disruption of stem cell function.

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    • "These results are remarkable given that the cells were delivered into the systemic vasculature and not directly into the brain. However, few surviving HUCB-derived cells were found in the brain of animals that received transplants [101] [102] [103] and fewer of these surviving cells expressed neural markers, indicating that replacement of lost neurons was not the primary mechanism inducing brain repair. In addition to producing growth/trophic factors, the HUCB mononuclear cells also produce a number of cytokines and chemokines.Indeed, we have consistently found that HUCB administration interrupts the inflammatory cascade observed in the aged brain reduces apoptotic cell death [104] and enhances neurogenesis and angiogenesis [105]. "
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    ABSTRACT: Age-related changes in innate immune function and glial-neuronal communication are early and critical events in brain aging and neurodegenerative disease, and lead to a chronic increase in oxidative stress and inflammation, which initiates neuronal dysfunction and reduced synaptic plasticity, and ultimately disruption in learning and memory in the aged brain. Several lines of evidence suggest a correlation between adult neurogenesis and learning. It has been proposed that a decline in hippocampal neurogenesis contributes to a physiologic decline in brain function. Recently, new and important insights relating to the production of new neurons affecting hippocampal-dependent memory ability have been provided. A multitude of factors have been shown to regulate the production of new neurons in the adult hippocampus, many of which change as a result of aging. Yet, the potential importance of neurogenesis in some affective and cognitive behaviors, as well as endogenous tissue repair mechanisms, makes further investigation of neurogenic regulators warranted. We have recent evidence that key regulators of communication between neurons and microglia are disrupted in the aged brain and may be one of the factors that precedes and initiates the observed increase in chronic inflammatory state. In this review the role of dysfunction in these neuronal-glial communication regulators underlying age-related impairments in cognition and hippocampal neurogenesis will be discussed. An understanding of these mechanisms will lead to the development of preventive or protective therapies.
    12/2010; 1(3):232-244.
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    • "On the contrary, the identification of critical extracellular factors that may have an impact on stem cell function could be addressed more easily. This approach has been successfully experimented both in the skeletal muscle, through the systemic delivery of a TGF-b receptor kinase inhibitor (Carlson et al., 2009), and in the hematopoietic system, by neutralization of the insulin-like growth factor-1 in the marrow microenvironment (Mayack et al., 2010). The positive impact of rosiglitazone on endothelial progenitor cells exposed to AGEs may be an additional example in this direction (Liang et al., 2009). "
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    ABSTRACT: Cellular senescence is a specialized form of growth arrest, confined to mitotic cells, induced by various stressful stimuli and characterized by a permanent growth arrest, resistance to apoptosis, an altered pattern of gene expression and the expression of some markers that are characteristic, although not exclusive, to the senescent state. Senescent cells profoundly modify neighboring and remote cells through the production of an altered secretome, eventually leading to inflammation, fibrosis and possibly growth of neoplastic cells. Mammalian aging has been defined as a reduction in the capacity to adequately maintain tissue homeostasis or to repair tissues after injury. Tissue homeostasis and regenerative capacity are nowadays considered to be related to the stem cell pool present in every tissue. For this reason, pathological and patho-physiological conditions characterized by altered tissue homeostasis and impaired regenerative capacity can be viewed as a consequence of the reduction in stem cell number and/or function. Last, cellular senescence is a double-edged sword, since it may inhibit the growth of transformed cells, preventing the occurrence of cancer, while it may facilitate growth of preneoplastic lesions in a paracrine fashion; therefore, interventions targeting this cell response to stress may have a profound impact on many age-related pathologies, ranging from cardiovascular disease to oncology. Aim of this review is to discuss both molecular mechanisms associated with stem cell senescence and interventions that may attenuate or reverse this process.
    Pharmacology [?] Therapeutics 10/2010; 129(1):3-20. DOI:10.1016/j.pharmthera.2010.10.005 · 7.75 Impact Factor
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    • "A criticism of this approach has been that transplantation requires 'conditioning' of the recipient (e.g., through wholebody irradiation) and therefore necessarily entails damage to the niche. The question of HSC aging has now been further pursued by the Wagers laboratory using parabiosis, which does not require conditioning (Mayack et al., 2010). As is the case with muscle stem cell function, the authors showed that a considerable component of HSC aging results from an aged stem cell niche. "
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    ABSTRACT: In many tissues, mammalian aging is associated with a decline in the replicative and functional capacity of somatic stem cells and other self-renewing compartments. Understanding the basis of this decline is a major goal of aging research. In particular, therapeutic approaches to ameliorate or reverse the age-associated loss of stem function could be of use in clinical geriatrics. Such approaches include attempts to protect stem cells from age-promoting damage, to 'rejuvenate' stem cells through the use of pharmacologic agents that mitigate aging-induced alterations in signaling, and to replace lost stem cells through regenerative medicine approaches. Some headway has been made in each of these arenas over the last 18 months including advances in the production of donor-specific totipotent stem cells through induced pluripotency (iPS), gains in our understanding of how tumor suppressor signaling is controlled in self-renewing compartments to regulate aging, and further demonstration of extracellular 'milieu' factors that perturb stem cell function with age. This period has also been marked by the recent award of the Nobel Prize in Physiology or Medicine for elucidation of telomeres and telomerase, a topic of critical importance to stem cell aging.
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