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The Softer, the Better - How Niche Stiffness Affects Aging Stem Cells

Review of “Niche stiffness underlies the ageing of central nervous system progenitor cells” from Nature by Stuart P. Atkinson

While studies have indicated that the loss of function of adult stem cell and progenitor cell populations causes a decline in tissue regeneration during aging [1], the reasons for this loss remain incompletely explained. Researchers from the laboratories of Robin J. M. Franklin and Kevin J. Chalut (University of Cambridge, Cambridge, UK) sought to define the factors that reduced the regenerative capacity of oligodendrocyte progenitor cells (OPCs) during aging [2] by evaluating alterations to the stem cell niche [3, 4]. 

In their fascinating new study, Segel et al. use varying culture substrates to demonstrate how an increase to the stiffness of the OPC niche can cause the age-related deterioration of function in a study that may aid the development of therapies for neurodegenerative diseases and the understanding the aging process [5]. Is softer better for OPCs in the rate brain?

The authors first established the importance of the niche by showing purified OPCs from aged rats recovered their lost activity following transplantation into their niche within the brains of neonatal rats (the prefrontal cortex) or when cultured on brain extracellular matrix derived from neonatal rats. To confirm their hypothesis that ECM stiffness may represent an important parameter, the authors confirmed that the OPC niche progressively stiffens with age with atomic force microscopy (AFM) and then demonstrated how OPCs grown on stiffer polyacrylamide hydrogels displayed a significant loss of activity when compared to OPCs cultured on soft hydrogels, while aged OPCs displayed signs of functional and molecular rejuvenation when cultured on soft hydrogels.

The study then focused on the mechanosensitive ion channel PIEZO1, whose inhibition reduces sensitivity to mechanical signals [6, 7], finding that Piezo1 gene and PIEZO1 protein expression increased with age, leading to high levels of PIEZO1 in aged OPCs. Interestingly, loss of PIEZO1 in OPC by short interfering RNA (siRNA) expression boosted the activity of aged OPCs cultured on stiff hydrogels, while neonatal OPCs stably expressing a Piezo1 short hairpin RNA (shRNA) displayed higher activity than control neonatal OPCs following transplantation into the aged prefrontal cortex. Furthermore,  PIEZO1 knockdown OPCs displayed a higher regenerative ability than wild type OPCs following induced focal demyelination in the white matter of aged mice. 

The authors hope that this new study will serve to highlight the consideration of the mechanical microenvironment in other aging pathways and suggest niche mechanics as the driving force behind aging in other adult stem cell systems. Is softer better for the niches of stem cells other than rat OPCs? 

For more on the importance of the stem cell niche, oligodendrocyte progenitor cells, and aging, stay tuned to the Stem Cells Portal!

References

  1. Goodell MA and Rando TA, Stem cells and healthy aging. Science 2015;350:1199.
  2. Sim FJ, Zhao C, Penderis J, et al., The Age-Related Decrease in CNS Remyelination Efficiency Is Attributable to an Impairment of Both Oligodendrocyte Progenitor Recruitment and Differentiation. The Journal of Neuroscience 2002;22:2451.
  3. Gopinath SD and Rando TA, Stem Cell Review Series: Aging of the skeletal muscle stem cell niche. Aging Cell 2008;7:590-598.
  4. Swift J, Ivanovska IL, Buxboim A, et al., Nuclear Lamin-A Scales with Tissue Stiffness and Enhances Matrix-Directed Differentiation. Science 2013;341:1240104.
  5. Segel M, Neumann B, Hill MFE, et al., Niche stiffness underlies the ageing of central nervous system progenitor cells. Nature 2019;573:130-134.
  6. McHugh BJ, Buttery R, Lad Y, et al., Integrin activation by Fam38A uses a novel mechanism of R-Ras targeting to the endoplasmic reticulum. Journal of Cell Science 2010;123:51.
  7. McHugh BJ, Murdoch A, Haslett C, et al., Loss of the Integrin-Activating Transmembrane Protein Fam38A (Piezo1) Promotes a Switch to a Reduced Integrin-Dependent Mode of Cell Migration. PLOS ONE 2012;7:e40346.