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Multipotent mesenchymal stromal cells (MSCs) are required for skeletal formation, maintenance, and repair throughout life; however, current models posit that postnatally arising long-lived adult MSCs replace transient embryonic progenitor populations. We previously reported exclusive expression and function of the embryonic patterning transcription factor, Hoxa11, in adult skeletal progenitor-enriched MSCs. Here, using a newly generated  Hoxa11-CreER   T2   lineage-tracing system, we show  Hoxa11 -lineage marked cells give rise to all skeletal lineages throughout the life of the animal and persist as MSCs.  Hoxa11  lineage-positive cells give rise to previously described progenitor-enriched MSC populations marked by  LepR-Cre  and  Osx-CreER , placing them upstream of these populations. Our studies establish that Hox-expressing cells are skeletal stem cells that arise from the earliest stages of skeletal development and self-renew throughout the life of the animal.

Hox11 expressing regional skeletal stem cells are progenitors for osteoblasts, chondrocytes and adipocytes throughout life