Transcriptome analysis of freshly isolated young and aged rat oligodendrocyte progenitor cells (OPCs)

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.年龄相关的少突胶质前体细胞（oligodendrocyte progenitor cells, OPCs）无法再生丢失的少突胶质细胞，这一表现与多发性硬化症中不可逆的神经退行性变密切相关。因此，针对慢性脱髓鞘疾病的再生治疗始终是学界长期追寻却难以实现的目标。 本研究发现，成年少突胶质前体细胞的固有分化潜能会随年龄增长逐渐丧失。此外，衰老的少突胶质前体细胞会丧失对促分化信号的响应能力，这极大限制了以增强少突胶质前体细胞分化为核心的髓鞘再生治疗效果。 本研究证实，这种再生能力的下降与细胞衰老的标志性特征紧密相关，包括代谢功能降低以及DNA损伤增多。我们发现，禁食或使用二甲双胍（metformin）治疗能够逆转上述变化，恢复衰老少突胶质前体细胞的再生能力，进而改善衰老动物在白质损伤后的髓鞘再生情况。 尤为重要的是，经二甲双胍处理的衰老少突胶质前体细胞可重新恢复对促分化因子的响应能力，这提示衰老逆转与促分化治疗或许存在协同效应。本研究结果为理解衰老过程中少突胶质细胞再生障碍的机制，以及如何通过治疗手段逆转这一病理过程提供了直接的理论依据。