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Peer-reviewedCC BY-NC 4.0Science Advances

Hoxa10 governs lifelong skeletal stem cell maintenance and bone repair

  • Kevin Leclerc1
  • Margaux Sambon1
  • Raven Weng1
  • Vincentius Jeremy Suhardi1
  • Malissa Ramsukh1
  • Rohan Phadke1
  • Gabrielle Pack1
  • Matthew Rytel2
  • Jack Zhong1
  • Benjamin Schaffler1
  • Sergio Butron1
  • Sophie M. Morgani1
1 more authors
  • Philipp Leucht1,2
  1. 1Department of Orthopedic Surgery, NYU Grossman School of Medicine, New York, NY, USA.
  2. 2Department of Cell Biology, NYU Grossman School of Medicine, New York, NY, USA.
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Abstract

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.

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Cite

BibTeXRIS
BibTeX
@article{leclerc2026hoxa10,
  title = {{Hoxa10 governs lifelong skeletal stem cell maintenance and bone repair}},
  author = {Kevin Leclerc and Margaux Sambon and Raven Weng and Vincentius Jeremy Suhardi and Malissa Ramsukh and Rohan Phadke and Gabrielle Pack and Matthew Rytel and Jack Zhong and Benjamin Schaffler and Sergio Butron and Sophie M. Morgani and Philipp Leucht},
  journal = {Science Advances},
  year = {2026},
  month = nov,
  doi = {10.1126/sciadv.aeg2088},
  url = {https://www.science.org/doi/abs/10.1126/sciadv.aeg2088},
  note = {CC BY-NC 4.0},
}
RIS
TY  - JOUR
TI  - Hoxa10 governs lifelong skeletal stem cell maintenance and bone repair
AU  - Kevin Leclerc
AU  - Margaux Sambon
AU  - Raven Weng
AU  - Vincentius Jeremy Suhardi
AU  - Malissa Ramsukh
AU  - Rohan Phadke
AU  - Gabrielle Pack
AU  - Matthew Rytel
AU  - Jack Zhong
AU  - Benjamin Schaffler
AU  - Sergio Butron
AU  - Sophie M. Morgani
AU  - Philipp Leucht
PY  - 2026
DA  - 2026/11/04
JO  - Science Advances
DO  - 10.1126/sciadv.aeg2088
UR  - https://www.science.org/doi/abs/10.1126/sciadv.aeg2088
AB  - 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.
SN  - 2375-2548
ER  -