Age-related loss of function in hematopoietic stem cells resident in the bone marrow is an important component of immune system aging, and thus important to aging as a whole. There is a tendency to think of cells only in terms of chemistry, but some of that chemistry is linked to structure, mechanical forces, and the physical properties of surrounding tissues. Researchers here find that RhoA, a key protein in a cell's response to mechanical stimulus, is important in loss of function in aged hematopoietic stem cells. It is something of an open question as to how much of this importance is driven by changes in the mechanical properties of surrounding tissues versus epigenetic changes inside the cell that affect its structure, but RhoA inhibition clearly restores some degree of lost hematopoietic function regardless of the precise details.
Biomechanical alterations contribute to the decreased regenerative capacity of hematopoietic stem cells (HSCs) upon aging. Mechanical forces trigger multiple signaling pathways that converge in the activation of RhoA, which is a small RhoGTPase that can cycle between an active (RhoA-GTP) and an inactive (RhoA-GDP) status. RhoA is a key regulator of mechanotransduction regardless of whether the activating mechanical stimulus is cell extrinsic, as occurs in cells responding to alterations of substrate stiffness, or cell intrinsic, such as, for example, when the cell nucleus acts as a mechanosensor of genomic changes.
Here we show that murine HSCs respond to increased nuclear envelope (NE) tension by inducing NE translocation of P-cPLA2, which cell-intrinsically activates RhoA. Aged HSCs experience physiologically higher intrinsic NE tension, but reducing RhoA activity lowers NE tension in aged HSCs. Feature image analysis of HSC nuclei reveals that chromatin remodeling is associated with RhoA inhibition, including restoration of youthful levels of the heterochromatin marker H3K9me2 and a decrease in chromatin accessibility and transcription at retrotransposons.
Finally, we demonstrate that RhoA inhibition upregulates Klf4 expression and transcriptional activity, improving aged HSC regenerative capacity and lymphoid/myeloid skewing in vivo. Together, our data outline an intrinsic RhoA-dependent mechanosignaling axis, which can be pharmacologically targeted to restore aged stem cell function.
Link: https://doi.org/10.1038/s43587-025-01014-w
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