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Single-cell analysis reveals fibroblast heterogeneity and myeloid-derived adipocyte progenitors in murine skin wounds.

  • Author(s): Guerrero-Juarez, Christian F
  • Dedhia, Priya H
  • Jin, Suoqin
  • Ruiz-Vega, Rolando
  • Ma, Dennis
  • Liu, Yuchen
  • Yamaga, Kosuke
  • Shestova, Olga
  • Gay, Denise L
  • Yang, Zaixin
  • Kessenbrock, Kai
  • Nie, Qing
  • Pear, Warren S
  • Cotsarelis, George
  • Plikus, Maksim V
  • et al.
Abstract

During wound healing in adult mouse skin, hair follicles and then adipocytes regenerate. Adipocytes regenerate from myofibroblasts, a specialized contractile wound fibroblast. Here we study wound fibroblast diversity using single-cell RNA-sequencing. On analysis, wound fibroblasts group into twelve clusters. Pseudotime and RNA velocity analyses reveal that some clusters likely represent consecutive differentiation states toward a contractile phenotype, while others appear to represent distinct fibroblast lineages. One subset of fibroblasts expresses hematopoietic markers, suggesting their myeloid origin. We validate this finding using single-cell western blot and single-cell RNA-sequencing on genetically labeled myofibroblasts. Using bone marrow transplantation and Cre recombinase-based lineage tracing experiments, we rule out cell fusion events and confirm that hematopoietic lineage cells give rise to a subset of myofibroblasts and rare regenerated adipocytes. In conclusion, our study reveals that wounding induces a high degree of heterogeneity among fibroblasts and recruits highly plastic myeloid cells that contribute to adipocyte regeneration.

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