A Dynamic Stem Cell State Links Environmental Cues to Skeletal and Regenerative Fates

Abstract

Stem cells faithfully generate tissue architecture during development, yet how their identity and regenerative output are reshaped as anatomical niches mature and environmental signals change with aging and injury remains poorly understood. Rare skeletal stem cells (SSCs) across diverse skeletal sites are defined by combinations of cell-surface markers, precluding their genetic interrogation in vivo. Here, using spatially informed single cell transcriptomics, we identify Pannexin-3 (Panx3) to mark a dynamic functional state within bona fide SSCs and establish Panx3-CreERT2 mice for its longitudinal interrogation. Panx3 SSCs exhibit long-term clonal persistence, self-renewal and multipotency, whereas Panx3- SSCs can acquire this state. Successive SSC cohorts engage the Panx3 state during skeletal development, osteoanabolic stimulation expands pre-existing Panx3 SSC clones and injury induces it locally in previously unlabeled progenitors. Thus, anatomically distinct progenitors can converge on a common stem cell state in response to different environmental inputs. Three-dimensional reconstruction of chondrogenic niches further identifies signals that redirect Panx3-lineage cells towards stable cartilage, enabling durable regeneration in aged and osteoarthritic joints and with human SSCs. These findings establish anatomical origin, stem cell state and lineage fate as separable dimensions of stem cell identity and provide genetic access for interrogating and directing endogenous SSC function.

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BibTeX RIS

BibTeX

@misc{wang2026dynamic,
  title = {{A Dynamic Stem Cell State Links Environmental Cues to Skeletal and Regenerative Fates}},
  author = {Y. Wang and L. Zhao and K. Chen and J. Xiang and E. J. Hunt and J. Sokol and K. Ding and H. M. Steininger and N. R. Martinez and K. C. Weldon and E. Chan and D. A. Morales and C. Martinez and S. Wang and G. Marquez-Arreguin and H. Chen and M. Y. Hoover and W.-J. Lu and J. Xiao and F. Guo and M. T. Longaker and I. L. Weissman and C. K. F. Chan and T. H. Ambrosi},
  howpublished = {bioRxiv},
  year = {2026},
  month = nov,
  doi = {10.64898/2026.11.04.764000},
  url = {https://www.biorxiv.org/content/10.64898/2026.11.04.764000v1},
  note = {CC BY-NC},
}

RIS

TY  - UNPB
TI  - A Dynamic Stem Cell State Links Environmental Cues to Skeletal and Regenerative Fates
AU  - Y. Wang
AU  - L. Zhao
AU  - K. Chen
AU  - J. Xiang
AU  - E. J. Hunt
AU  - J. Sokol
AU  - K. Ding
AU  - H. M. Steininger
AU  - N. R. Martinez
AU  - K. C. Weldon
AU  - E. Chan
AU  - D. A. Morales
AU  - C. Martinez
AU  - S. Wang
AU  - G. Marquez-Arreguin
AU  - H. Chen
AU  - M. Y. Hoover
AU  - W.-J. Lu
AU  - J. Xiao
AU  - F. Guo
AU  - M. T. Longaker
AU  - I. L. Weissman
AU  - C. K. F. Chan
AU  - T. H. Ambrosi
PY  - 2026
DA  - 2026/11/04
PB  - bioRxiv
DO  - 10.64898/2026.11.04.764000
UR  - https://www.biorxiv.org/content/10.64898/2026.11.04.764000v1
AB  - Stem cells faithfully generate tissue architecture during development, yet how their identity and regenerative output are reshaped as anatomical niches mature and environmental signals change with aging and injury remains poorly understood. Rare skeletal stem cells (SSCs) across diverse skeletal sites are defined by combinations of cell-surface markers, precluding their genetic interrogation in vivo. Here, using spatially informed single cell transcriptomics, we identify Pannexin-3 (Panx3) to mark a dynamic functional state within bona fide SSCs and establish Panx3-CreERT2 mice for its longitudinal interrogation. Panx3 SSCs exhibit long-term clonal persistence, self-renewal and multipotency, whereas Panx3- SSCs can acquire this state. Successive SSC cohorts engage the Panx3 state during skeletal development, osteoanabolic stimulation expands pre-existing Panx3 SSC clones and injury induces it locally in previously unlabeled progenitors. Thus, anatomically distinct progenitors can converge on a common stem cell state in response to different environmental inputs. Three-dimensional reconstruction of chondrogenic niches further identifies signals that redirect Panx3-lineage cells towards stable cartilage, enabling durable regeneration in aged and osteoarthritic joints and with human SSCs. These findings establish anatomical origin, stem cell state and lineage fate as separable dimensions of stem cell identity and provide genetic access for interrogating and directing endogenous SSC function.
ER  -

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