Aijun Hao’s research while affiliated with Institute of Basic Medical Sciences of the Chinese Academy of Medical Sciences and other places

Demyelination occurs widely in the central nervous system (CNS) neurodegenerative diseases, especially the multiple sclerosis (MS), which with a complex and inflammatory lesion microenvironment inhibiting remyelination. Sirtuin6 (SIRT6), a histone/protein deacetylase is of interest for its promising effect in transcriptional regulation, cell cycling, inflammation, metabolism and longevity. Here we show that SIRT6 participates in the remyelination process in mice subjected to LPC-induced demyelination. Using pharmacological SIRT6 inhibitor or activator, we found that SIRT6 modulated LPC-induced damage in motor or cognitive function. Inhibition of SIRT6 impaired myelin regeneration, exacerbated neurological deficits, and decreased oligodendrocyte precursor cells (OPCs) proliferation and differentiation, whereas activation of SIRT6 reversed behavioral performance in mice, demonstrating a beneficial effect of SIRT6. Importantly, based on RNA sequencing analysis of the corpus callosum tissues, it was further revealed that SIRT6 took charge in regulation of glial activation during remyelination, and significant alterations in CHI3L1 were obtained, a glycoprotein specifically secreted by astrocytes. Impaired proliferation and differentiation of OPCs could be induced in vitro using supernatants from reactive astrocyte, especially when SIRT6 was inhibited. Mechanistically, SIRT6 regulates the secretion of CHI3L1 from reactive astrocytes by histone-H3-lysine-9 acetylation (H3K9Ac). Adeno-associated virus-overexpression of SIRT6 (AAV-SIRT6-OE) in astrocytes improved remyelination and functional recovery after LPC-induced demyelination, whereas together with AAV-CHI3L1-OE inhibits this therapeutic effect. Collectively, our data elucidate the role of SIRT6 in remyelination and further reveal astrocytic SIRT6/CHI3L1 as the key regulator for improving the remyelination environment, which may be a potential target for MS therapy.

Background White matter injury is a predominant form of brain injury in preterm infants. However, effective drugs for its treatment are currently lacking. Previous studies have shown the neuroprotective effects of Isoliquiritigenin (ISL), but its impact on white matter injury in preterm infants remains poorly understood. Aims This study aimed to investigate the protective effects of ISL against white matter injury caused by infection in preterm infants using a mouse model of lipopolysaccharide-induced white matter injury, integrating network pharmacology as well as in vivo and in vitro experiments. Methods This study explores the potential mechanisms of ISL on white matter injury by integrating network pharmacology. Core pathways and biological processes affected by ISL were verified through experiments, and motor coordination, anxiety-like, and depression-like behaviors of mice were evaluated using behavioral experiments. White matter injury was observed using hematoxylin-eosin staining, Luxol Fast Blue staining, and electron microscopy. The development of oligodendrocytes and the activation of microglia in mice were assessed by immunofluorescence. The expression of related proteins was detected by Western blot. Results We constructed a drug-target network, including 336 targets associated with ISL treatment of white matter injury. The biological process of ISL treatment of white matter injury mainly involves microglial inflammation regulation and myelination. Our findings revealed that ISL reduced early nerve reflex barriers and white matter manifestations in mice, leading to decreased activation of microglia and release of proinflammatory cytokines. Additionally, ISL demonstrated the ability to mitigate impairment in oligodendrocyte development and myelination, ultimately improving behavior disorders in adult mice. Mechanistically, we observed that ISL downregulated HDAC3 expression, promoted histone acetylation, enhanced the expression of H3K27ac, and regulated oligodendrocyte pro-differentiation factors. Conclusion These findings suggest that ISL can have beneficial effects on white matter injury in preterm infants by alleviating inflammation and promoting oligodendrocyte differentiation.

Epigenetics plays a crucial role in regulating gene expression during adolescent brain maturation. In adolescents with depression, microglia-mediated chronic neuroinflammation may contribute to the activation of cellular signaling cascades and cause central synapse loss. However, the exact mechanisms underlying the epigenetic regulation of neuroinflammation leading to adolescent depression remain unclear. In this study, we found that the expression of polycomb group 1 (PCGF1), an important epigenetic regulator, was decreased both in the plasma of adolescent major depressive disorder (MDD) patients and in the microglia of adolescent mice in a mouse model of depression. We demonstrated that PCGF1 alleviates neuroinflammation mediated by microglia in vivo and in vitro, reducing neuronal damage and improving depression-like behavior in adolescent mice. Mechanistically, PCGF1 inhibits the transcription of MMP10 by upregulating RING1B/H2AK119ub and EZH2/H3K27me3 in the MMP10 promoter region, specifically inhibiting microglia-mediated neuroinflammation. These results provide valuable insights into the pathogenesis of adolescent depression, highlighting potential links between histone modifications, neuroinflammation and nerve damage. Potential mechanisms of microglial PCGF1 regulates depression-like behavior in adolescent mice. Microglial PCGF1 inhibits NF-κB/MAPK pathway activation through regulation of RING1B/H2AK119ub and EZH2/H3K27me3 in the MMP10 promoter region, which attenuates neuroinflammation and ameliorates depression-like behaviors in adolescent mice.

Electrical stimulation holds promise for enhancing neuronal differentiation of neural stem cells to treat traumatic brain injury. However, once the stem cells leave the stimulating material and migrate post transplantation, electrical stimulation on them is diminished. Here, we wrap the stem cells with wireless electrical nanopatches, the conductive graphene nanosheets. Under electromagnetic induction, electrical stimulation can thus be applied in-situ to individual nanopatch-wrapped stem cells on demand, stimulating their neuronal differentiation through a MAPK/ERK signaling pathway. Consequently, 41% of the nanopatch-wrapped stem cells differentiate into functional neurons in 5 days, as opposed to only 16.3% of the unwrapped ones. The brain injury male mice implanted with the nanopatch-wrapped stem cells and exposed to a rotating magnetic field 30 min/day exhibit significant recovery of brain tissues, behaviors, and cognitions, within 28 days. This study opens up an avenue to individualized electrical stimulation of transplanted stem cells for treating neurodegenerative diseases.

Parkinson's disease (PD) is a debilitating neurodegenerative disorder characterized by dopaminergic neuron degeneration. Neural stem cell (NSC) therapy offers promise for replacing these neurons and restoring neural function. However, directing NSCs to become dopaminergic neurons is challenging. Retinoic acid (RA) is a potential regulator, but its insolubility in water limits its use in PD therapy. Herein, nanonizing RA with calcium acetate to create calcium‐retinoic acid nanoparticles (Ca‐RA NPs) is proposed. These nanoparticles can be internalized by NSCs and then dissociated in the acidic environment of lysosomes to lead to a burst of Ca²⁺ and RA. In vitro results showed that the intracellular bursting of Ca²⁺ and RA accelerated neuronal differentiation and maturation by 5–10 days compared to spontaneous NSC differentiation. Importantly, Ca‐RA NPs uniquely directed NSCs to dopaminergic neurons, involving the interaction between the calcium ion‐mediated MAPK signaling pathway and the RA‐mediated RA signaling pathway. Animal experiments further validated the efficacy of Ca‐RA‐coated NSCs in restoring motor and cognitive functions in PD mice by rapidly forming dopaminergic neural circuits. Given that both RA and calcium acetate are approved by the FDA, this strategy has the potential for translation into a clinical treatment approach for stem cell therapy of PD.

Polycomb group RING finger (PCGF) proteins, a crucial subunits of the Polycomb complex, plays an important role in regulating gene expression, embryonic development, and cell fate determination. In our research, we investigated Pcgf5, one of the six PCGF homologs, and its impact on the differentiation of P19 cells into neural stem cells. Our findings revealed that knockdown of Pcgf5 resulted in a significant decrease in the expression levels of the neuronal markers Sox2, Zfp521, and Pax6, while the expression levels of the pluripotent markers Oct4 and Nanog increased. Conversely, Pcgf5 overexpression upregulated the expression of Sox2 and Pax6, while downregulating the expression of Oct4 and Nanog. Additionally, our analysis revealed that Pcgf5 suppresses Wnt3 expression via the activation of Notch1/Hes1, and ultimately governs the differentiation fate of neural stem cells. To further validate our findings, we conducted in vivo experiments in zebrafish. We found that knockdown of pcgf5a using morpholino resulted in the downregulated expression of neurodevelopmental genes such as sox2, sox3, and foxg1 in zebrafish embryos. Consequently, these changes led to neurodevelopmental defects. In conclusion, our study highlights the important role of Pcgf5 in neural induction and the determination of neural cell fate.

Controlling the nanoparticle‐cell membrane interaction to achieve easy and fast membrane anchoring and cellular internalization is of great importance in a variety of biomedical applications. Here we report a simple and versatile strategy to maneuver the nanoparticle‐cell membrane interaction by creating a tunable hydrophobic protrusion on Janus particles through swelling‐induced symmetry breaking. When the Janus particle contacts cell membrane, the protrusion will induce membrane wrapping, leading the particles to docking to the membrane, followed by drawing the whole particles into the cell. The efficiencies of both membrane anchoring and cellular internalization can be promoted by optimizing the size of the protrusion. In vitro, the Janus particles can quickly anchor to the cell membrane in 1 h and be internalized within 24 h, regardless of the types of cells involved. In vivo, the Janus particles can effectively anchor to the brain and skin tissues to provide a high retention in these tissues after intracerebroventricular, intrahippocampal, or subcutaneous injection. This strategy involving the creation of a hydrophobic protrusion on Janus particles to tune the cell‐membrane interaction holds great potential in nanoparticle‐based biomedical applications.

Controlling the nanoparticle‐cell membrane interaction to achieve easy and fast membrane anchoring and cellular internalization is of great importance in a variety of biomedical applications. Here we report a simple and versatile strategy to maneuver the nanoparticle‐cell membrane interaction by creating a tunable hydrophobic protrusion on Janus particles through swelling‐induced symmetry breaking. When the Janus particle contacts cell membrane, the protrusion will induce membrane wrapping, leading the particles to docking to the membrane, followed by drawing the whole particles into the cell. The efficiencies of both membrane anchoring and cellular internalization can be promoted by optimizing the size of the protrusion. In vitro, the Janus particles can quickly anchor to the cell membrane in 1 h and be internalized within 24 h, regardless of the types of cells involved. In vivo, the Janus particles can effectively anchor to the brain and skin tissues to provide a high retention in these tissues after intracerebroventricular, intrahippocampal, or subcutaneous injection. This strategy involving the creation of a hydrophobic protrusion on Janus particles to tune the cell‐membrane interaction holds great potential in nanoparticle‐based biomedical applications.