Myc determines the functional age state of oligodendrocyte progenitor cells

Like many adult stem cell populations, the capacity of oligodendrocyte progenitor cells (OPCs) to proliferate and differentiate is significantly impaired with ageing. Previous work has shown that tissue-wide transient expression of the pluripotency factors Oct4, Sox2, Klf4 and c-Myc extends lifespan and enhances somatic cell function. Here we show that just one of these factors, c-Myc, is sufficient to determine the age state of the OPC: c-Myc expression in aged OPCs drives their functional rejuvenation, while inhibition of c-Myc in neonatal OPCs induces an aged-like phenotype, as determined by in vitro assays and transcriptome analysis. We show that increasing c-Myc expression specifically in aged OPCs in vivo restores their proliferation and differentiation capacity, thereby enhancing regeneration in an otherwise aged CNS environment. More generally, our results directly link Myc to cellular activity and cell age-state, with implications for understanding regeneration in the context of ageing and provide important insights into the biology of stem cell ageing.

与多数成体干细胞群体类似，少突胶质细胞祖细胞（oligodendrocyte progenitor cells, OPCs）的增殖与分化能力会随衰老进程显著受损。既往研究表明，在全组织中瞬时表达多能性因子（pluripotency factors）Oct4、Sox2、Klf4及c-Myc，可延长生物体寿命并改善体细胞功能。本研究发现，仅需上述因子中的c-Myc即可决定OPCs的衰老状态：在衰老OPCs中表达c-Myc可推动其功能年轻化，而在新生OPCs中抑制c-Myc则会诱导出衰老样表型，该结论通过体外实验与转录组分析得以证实。本研究还证实，在体内特异性上调衰老OPCs的c-Myc表达水平，可恢复其增殖与分化能力，进而在本已衰老的中枢神经系统（central nervous system, CNS）微环境中提升组织再生能力。从更广泛的层面来看，本研究结果将Myc与细胞活性及细胞衰老状态直接关联，为理解衰老背景下的组织再生提供了理论依据，并为干细胞衰老生物学研究提供了重要见解。