Ibec Seminar. M. Carolina Florian
Targeting RhoA mechanoactivity rejuvenates aged hematopoietic stem cells
Mechanical alterations contribute to the decreased regenerative capacity of hematopoietic stem cells (HSCs) upon aging. RhoA is a key regulator of mechanosignaling, but its role in mechanotransduction in stem cell aging remains unclear. Recently we have demonstrated that RhoA is activated by increasing nuclear envelope (NE) tension by cell confinement and by osmotic shock. Interestingly, our data show that aged HSCs experience physiologically higher intrinsic NE tension and RhoA activation. We show that pharmacological inhibition of RhoA activity lowers NE tension in aged HSCs. Feature image analysis of HSC nuclei reveals that an aged dependent chromatin remodeling is responsible of higher NE tension levels upon aging. Moreover, our data show that RhoA inhibition restores youthful levels of the heterochromatin marker H3K9me2 in aged HSCs and decreases chromatin accessibility and transcription at retrotransposons. Finally, we demonstrated that RhoA inhibition in aged HSCs upregulates Klf4 expression and transcriptional activity, improving aged HSC regenerative capacity and lympho-myeloid skewing in vivo. Together, our data outline an intrinsic RhoA-dependent mechanosignaling axis in HSCs, which can be pharmacologically targeted to restore aged stem cell function.
