A Senescence-Resistant Mesenchymal Progenitor Cell Sustains Tissue Homeostasis In Ageing

The functional decline of mesenchymal stromal/progenitor cells (MSCs) is a central driver of skeletal ageing, leading to osteoporosis and impaired regeneration. However, the prevailing view of a uniformly ageing MSC pool may be incomplete. This study identifies and characterizes a rare subpopulation of mesenchymal progenitors with innate senescence resistance, which we term Senescence-Resistant Committed progenitors (SRCs). Isolated from aged murine and human tissues via a unique surface phenotype (CD45ˉCD31ˉCD34ˉCD73+CD90+CD105+CD200+ITGA10+), SRCs demonstrate remarkable numerical preservation compared to severely depleted classical MSCs. Functionally, aged SRCs maintain low levels of senescence markers (p16INK4a, SA-β-gal), lack a pro-inflammatory secretome, and retain high clonogenic and proliferative potential. Crucially, they preserve a robust osteogenic differentiation capacity, countering the age-related adipogenic shift. Transcriptomic and epigenetic profiling reveals that SRC resilience is underpinned by constitutive activation of DNA repair, antioxidant defense (NRF2), and mitochondrial homeostasis pathways, stabilized by a protective epigenetic landscape featuring CDKN2A/p16 promoter hypomethylation. In vivo, transplantation of aged SRCs significantly enhances bone regeneration in critical-sized defects compared to aged bulk MSCs. The discovery of SRCs reframes mesenchymal ageing, revealing a resilient cellular reservoir essential for tissue homeostasis. Targeting the SRC pool or mimicking its molecular signature represents a novel therapeutic frontier for age-related skeletal disorders.