Brain Tissue Stiffening Causes Age-Related Stem Cell Dysfunction

New research suggests increasing brain stiffness as we age causes brain stem cell dysfunction and this loss of function may be reversible.

Researchers at the Wellcome-MRC Cambridge Stem Cell Institute investigated how age-related mechanical changes to the stem cell niche plays a role in the loss of function of oligodendrocyte progenitor cells (OPC), brain stem cells important for maintaining normal brain function and for the regeneration of myelin.

The activity of OPCs seem to be regulated by the stiffness of their surroundings. Isolated OPCs were grown on hydrogels that mimic the stiffening of the brain extracellular matrix with age. When aged OPCs were plated on soft hydrogels that mimic the stiffness of young brains, their ability to proliferate and differentiate increased more than tenfold. On the other hand, young OPCs lost their capacity to proliferate and differentiate on stiff hydrogels.

This study also demonstrated that age-related loss of stem cell function can be restored by blocking the mechanism by which OPCs sense stiffness. PIEZO1 was identified as a key mediator of OPC mechanical signalling, and both Piezo1 gene and PIEZO1 protein expression were also found to increase with age. siRNA knockdown of this mechanoresponsive ion channel in rats successfully ‘deceived’ OPCs into functioning as if they are in a softer environment and they continued to proliferate despite being transplanted into an aged microenvironment.

The findings of this study, and others that have observed unique regional brain stiffness patterns in different dementia subtypes, suggest that tissue mechanics is a more important determinant of brain health than previously thought. Future research should focus on investigating the underlying causes of increasing stiffness of brain tissue in stem cell niches in the ageing brain, and whether niche mechanics is a general factor that drives ageing in other stem cell populations.