Transcriptomics of mouse oligodendrocyte precursor cells treated with microglia-derived extracellular vesicles
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE304130 | GEO | 2025/10/21
REPOSITORIES: GEO
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Project description:Following CNS demyelination, adult oligodendrocyte progenitor cells (OPCs) can differentiate into new myelin-forming oligodendrocytes in a regenerative process called remyelination. While remyelination is very efficient in young adults, its efficiency declines progressively with ageing. Here we performed proteomic analysis on OPCs isolated acutely from the brains of neonate, young and aged female rats. Approximately 60% of the proteins are expressed at different levels in OPCs from neonates compared to their adult counterparts. The amount of myelin-associated and cell adhesion proteins are increased with age, while cholesterol-biosynthesis, transcription factors and cell cycle proteins decreased. Our experiments provide the first ageing OPC rodent proteome, revealing the distinct features of neonatal and adult OPCs, and providing new insights into why remyelination efficiency declines with ageing and potential roles for aged OPCs in other neurodegenerative diseases.
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Project description:Following CNS demyelination, adult oligodendrocyte progenitor cells (OPCs) can differentiate into new myelin-forming oligodendrocytes in a regenerative process called remyelination. While remyelination is very efficient in young adults, its efficiency declines progressively with ageing. Here we performed proteomic analysis on OPCs isolated acutely from the brains of neonate, young and aged female rats. Approximately 60% of the proteins are expressed at different levels in OPCs from neonates compared to their adult counterparts. The amount of myelin-associated and cell adhesion proteins are increased with age, while cholesterol-biosynthesis, transcription factors and cell cycle proteins decreased. Our experiments provide the first ageing OPC rodent proteome, revealing the distinct features of neonatal and adult OPCs, and providing new insights into why remyelination efficiency declines with ageing and potential roles for aged OPCs in other neurodegenerative diseases.
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Project description:The function of poly(ADP-ribosyl) polymerase 1 (PARP1) in myelination and remyelination of the central nervous system (CNS) remains enigmatic. Here we report that PARP1 is an intrinsic driver for oligodendroglial development and myelination. Genetic PARP1 depletion impairs the differentiation of oligodendrocyte progenitor cells (OPCs) into oligodendrocytes and impedes CNS myelination. Mechanistically, PARP1-mediated PARylation activity is not only necessary but also sufficient for OPC differentiation. At the molecular level, we identify the RNA-binding protein Myef2 as a PARylated target which controls OPC differentiation through PARylation-modulated de-repression of myelin protein expression. Furthermore, PARP1’s enzymatic activity is necessary for oligodendrocyte and myelin regeneration after demyelination. Together, our findings suggest that PARP1-mediated PARylation activity may be a potential therapeutic target for promoting OPC differentiation and remyelination in neurological disorders characterized by arrested OPC differentiation and remyelination failure such as multiple sclerosis.
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Project description:Microglia, the resident immune cells of the central nervous system (CNS), are important regulators of normal brain activities. In CNS demyelinating diseases like multiple sclerosis (MS), the functions of these cells are of particular interest. Based on the observation of diminished Dicer positive microglia/macrophages number in demyelinating white matter lesions (WMLs) of human MS brains, here we probed the impact of impaired microRNA (miRNA)-mediated post-transcriptional gene regulation in a mouse model lacking microglia/macrophage-specific Dicer1 expression during demyelination and remyelination. Conditional Dicer1 ablation and loss of miRNAs expression in adult microglia led to extensive demyelination and impaired myelin processing. Interestingly, demyelination was accompanied by increased apoptosis of mature oligodendrocytes (OLs) and arresting oligodendrocyte progenitor cells (OPCs) in the precursor stage. At the transcriptional level, Dicer1-deficient microglia led to downregulation of microglial homeostatic genes, increased cell proliferation, and a shift towards a disease-associated phenotype. Loss of remyelination efficiency in these mice was accompanied by stalling of OPCs in the precursor stage. Collectively, finding from this study highlight a new role of microglial miRNAs in promoting a pro-regenerative phenotype in addition to promoting OPC maturation and differentiation during demyelination and remyelination.
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Project description:Multiple sclerosis (MS) is characterized by demyelinated lesions in the central nervous system. Destruction of myelin and secondary damage to axons and neurons leads to significant disability, particularly in people with progressive MS. Accumulating evidence suggests that the potential for myelin repair exists in MS, although for unclear reasons this process fails. The cells responsible for producing myelin, the oligodendrocytes, and their progenitors oligodendrocyte precursor cells (OPCs) have been identified at the site of lesions, even in adults. Their presence suggests the possibility that endogenous remyelination without transplantation of donor stem cells may be a strategy for myelin repair in MS. Strategies to develop novel therapies have focused on induction of signaling pathways that stimulate OPCs to mature into myelin-producing oligodendrocytes that could then possibly remyelinate lesions. We have been investigating pharmacological approaches to enhance OPC differentiation, and have identified that the combination of two agents, triiodothyronine (T3) and quetiapine, leads to an additive effect on OPC differentiation and consequent myelin production via both overlapping and distinct signaling pathways. While the ultimate production of myelin requires cholesterol biosynthesis, we identified that quetiapine enhances gene expression in this pathway more potently than T3. Two blockers of cholesterol production, betulin and simvastatin, reduced OPC differentiation into myelin producing oligodendrocytes. Elucidating the nature of agents that lead to complementary and additive effects, possibly even synergistic effects, on oligodendrocyte differentiation and myelin production may pave the way for more efficient induction of remyelination in people with MS.
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Project description:The age-related failure to regenerate lost oligodendrocytes from oligodendrocyte progenitor cells (OPCs) is associated with irreversible neurodegeneration in multiple sclerosis. Consequently, regenerative therapies for chronic demyelinating diseases remain a long sought after but elusive goal. Here we show that adult OPCs lose their inherent differentiation potential with increasing age. Moreover, aged OPCs do not remain responsive to pro-differentiation signals, posing significant constraints on the effectiveness of remyelination therapies based on the enhancement of OPC differentiation. We show that this reduced regenerative capacity is associated with hallmarks of cellular ageing, including reduced metabolic function and increased DNA damage. We find that fasting or treatment with metformin can reverse these changes and restore the regenerative capacity of aged OPCs, improving remyelination in aged animals following white matter injury. Importantly, aged OPCs treated with metformin regain their responsiveness to pro-differentiation factors, suggesting a potential for synergistic effects of rejuvenation and pro-differentiation therapies. Our findings have direct implications for understanding oligodendrocyte regeneration failure with ageing and how it might be reversed therapeutically.
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