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Niche stiffness underlies the ageing of central nervous system progenitor cells

机译：生态位僵硬是中枢神经系统祖细胞衰老的基础

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摘要

Ageing causes a decline in tissue regeneration owing to a loss of function of adult stem cell and progenitor cell populations(1). One example is the deterioration of the regenerative capacity of the widespread and abundant population of central nervous system (CNS) multipotent stem cells known as oligodendrocyte progenitor cells (OPCs)(2). A relatively overlooked potential source of this loss of function is the stem cell 'niche'-a set of cell-extrinsic cues that include chemical and mechanical signals(3,4). Here we show that the OPC microenvironment stiffens with age, and that this mechanical change is sufficient to cause age-related loss of function of OPCs. Using biological and synthetic scaffolds to mimic the stiffness of young brains, we find that isolated aged OPCs cultured on these scaffolds are molecularly and functionally rejuvenated. When we disrupt mechanical signalling, the proliferation and differentiation rates of OPCs are increased. We identify the mechanoresponsive ion channel PIEZO1 as a key mediator of OPC mechanical signalling. Inhibiting PIEZO1 overrides mechanical signals in vivo and allows OPCs to maintain activity in the ageing CNS. We also show that PIEZO1 is important in regulating cell number during CNS development. Thus we show that tissue stiffness is a crucial regulator of ageing in OPCs, and provide insights into how the function of adult stem and progenitor cells changes with age. Our findings could be important not only for the development of regenerative therapies, but also for understanding the ageing process itself.
机译：由于成年干细胞和祖细胞群功能的丧失，衰老会导致组织再生下降（1）。一个例子是称为少突胶质细胞祖细胞（OPC）的中枢神经系统（CNS）多能干细胞的广泛和丰富种群的再生能力下降（2）。这种功能丧失的一个相对被忽视的潜在来源是干细胞“小生境”（niche）-一组细胞外源性线索，包括化学和机械信号（3,4）。在这里，我们显示OPC的微环境会随着年龄的增长而变硬，并且这种机械变化足以引起与年龄相关的OPC的功能丧失。使用生物和合成支架模拟年轻人的大脑僵硬，我们发现，在这些支架上培养的孤立的老年OPC可在分子和功能上恢复活力。当我们破坏机械信号传递时，OPC的增殖和分化速率会增加。我们确定机械响应离子通道PIEZO1是OPC机械信号传递的关键介体。抑制PIEZO1会覆盖体内的机械信号，并使OPC在衰老的CNS中保持活性。我们还表明，PIEZO1在中枢神经系统发育过程中对调节细胞数很重要。因此，我们表明组织刚度是OPCs衰老的关键调节器，并提供有关成年干细胞和祖细胞功能如何随年龄变化的见解。我们的发现不仅对再生疗法的发展很重要，而且对衰老过程本身的理解也很重要。

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