Hoxa10 governs lifelong skeletal stem cell maintenance and bone repair

Skeletal stem and progenitor cells (SSPCs) sustain bone homeostasis and regeneration throughout life, yet the transcriptional programs that preserve their identity remain poorly defined. Here we identify the distal Hox gene Hoxa10 as a cell-autonomous regulator of skeletal stem cell maintenance. Using inducible genetic deletion, lineage tracing, single-cell transcriptomics, and injury models, we show that loss of Hoxa10 leads to progressive depletion of SSPCs, impaired bone regeneration, and defective matrix organization. Mechanistically, Hoxa10 maintains the undifferentiated state of skeletal stem cells by restraining premature osteogenic, adipogenic, and chondrogenic commitment, while promoting collagen III production and collagen fiber alignment within regenerative niches. Hoxa10 -dependent regulation of extracellular matrix composition is restricted to primitive progenitors and is uncoupled from osteoblast differentiation. Notably, transient depletion of distal Hox genes in primary human SSPCs recapitulates the murine defects in proliferation, self-renewal, and differentiation restraint. Together, these findings define a conserved Hox-dependent program that preserves skeletal stem cell identity and regenerative competence, revealing how developmental transcription factors are repurposed to sustain the adult skeleton across the life span.