Single-cell mapping of regenerative and fibrotic healing responses after musculoskeletal injury

Robert J. Tower*, Alec C. Bancroft, Ashish R. Chowdary, Spencer Barnes, Nicole J. Edwards, Chase A. Pagani, Lindsay A. Dawson, Benjamin Levi*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


After injury, a cascade of events repairs the damaged tissue, including expansion and differentiation of the progenitor pool and redeposition of matrix. To guide future wound regeneration strategies, we compared single-cell sequencing of regenerative (third phalangeal element [P3]) and fibrotic (second phalangeal element [P2]) digit tip amputation (DTA) models as well as traumatic heterotopic ossification (HO; aberrant). Analyses point to a common initial response to injury, including expansion of progenitors, redeposition of matrix, and activation of transforming growth factor β (TGF-β) and WNT pathways. Surprisingly, fibrotic P2 DTA showed greater transcriptional similarity to HO than to regenerative P3 DTA, suggesting that gene expression more strongly correlates with healing outcome than with injury type or cell origin. Differential analysis and immunostaining revealed altered activation of inflammatory pathways, such as the complement pathway, in the progenitor cells. These data suggests that common pathways are activated in response to damage but are fine tuned within each injury. Modulating these pathways may shift the balance toward regenerative outcomes.

Original languageEnglish
Pages (from-to)2334-2348
Number of pages15
JournalStem Cell Reports
Issue number10
StatePublished - 11 Oct 2022
Externally publishedYes


  • digit tip amputation
  • fibrosis
  • heterotopic ossification
  • injury repair
  • mesenchymal progenitor cells
  • regeneration


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