Niche stiffness underlies the ageing of central nervous system progenitor cells

Michael Segel, Björn Neumann, Myfanwy F. E. Hill, Isabell P. Weber, Carlo Viscomi, Chao Zhao, Adam Young, Chibeza C. Agley, Amelia J. Thompson, Ginez A. Gonzalez, Amar Sharma, Staffan Holmqvist, David H. Rowitch, Kristian Franze, Robin J. M. Franklin () and Kevin J. Chalut ()
Additional contact information
Michael Segel: University of Cambridge
Björn Neumann: University of Cambridge
Myfanwy F. E. Hill: University of Cambridge
Isabell P. Weber: University of Cambridge
Carlo Viscomi: University of Cambridge
Chao Zhao: University of Cambridge
Adam Young: University of Cambridge
Chibeza C. Agley: University of Cambridge
Amelia J. Thompson: University of Cambridge
Ginez A. Gonzalez: University of Cambridge
Amar Sharma: University of Cambridge
Staffan Holmqvist: University of Cambridge
David H. Rowitch: University of Cambridge
Kristian Franze: University of Cambridge
Robin J. M. Franklin: University of Cambridge
Kevin J. Chalut: University of Cambridge

Nature, 2019, vol. 573, issue 7772, 130-134

Abstract: Abstract Ageing causes a decline in tissue regeneration owing to a loss of function of adult stem cell and progenitor cell populations1. 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 signals3,4. 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.

Date: 2019
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DOI: 10.1038/s41586-019-1484-9

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