Niche stiffness underlies the aging of central nervous system progenitor cells

Aging causes a decline in tissue regeneration due to a loss of function in adult stem and progenitor cell populations(1). An important 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 for this loss of function is the stem cell niche, a source of cell-extrinsic cues including chemical and mechanical signalling(3,4). In this study, we show that the OPC microenvironment stiffens with age, and that this stiffening is sufficient to cause age-related OPC loss of function. Using biological and novel synthetic scaffolds to mimic the stiffness of young brain we find that isolated aged OPCs (aOPCs) cultured on these scaffolds are molecularly and functionally rejuvenated. When we disrupt mechanical signalling, OPC proliferation and differentiation rates are increased. We identify the mechanoresponsive ion channel Piezo1 as a key mediator of OPC mechanical signalling. Inhibition of Piezo1 overrides mechanical signals in vivo and allows OPCs to maintain activity in the aging CNS. We also show that Piezo1 plays an important role in regulating cell number during CNS development. Thus, we show that tissue stiffness is an important regulator of aging in OPCs, and provide new insights into how adult stem and progenitor cell function changes with age. These findings are of fundamental importance not only for the development of regenerative therapies but also for understanding the aging process itself.