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

Christian F. Guerrero-Juarez, Priya H. Dedhia, Suoqin Jin, Rolando Ruiz-Vega, Dennis Ma, Yuchen Liu, Kosuke Yamaga, Olga Shestova, Denise L. Gay, Zaixin Yang, Kai Kessenbrock, Qing Nie, Warren S. Pear, George Cotsarelis () and Maksim V. Plikus ()
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Christian F. Guerrero-Juarez: University of California, Irvine
Priya H. Dedhia: University of Pennsylvania
Suoqin Jin: University of California, Irvine
Rolando Ruiz-Vega: University of California, Irvine
Dennis Ma: University of California, Irvine
Yuchen Liu: University of California, Irvine
Kosuke Yamaga: University of California, Irvine
Olga Shestova: University of Pennsylvania
Denise L. Gay: CEA/INSERM Inserm_U967
Zaixin Yang: Perelman School of Medicine at the University of Pennsylvania
Kai Kessenbrock: University of California, Irvine
Qing Nie: University of California, Irvine
Warren S. Pear: University of Pennsylvania
George Cotsarelis: Perelman School of Medicine at the University of Pennsylvania
Maksim V. Plikus: University of California, Irvine

Nature Communications, 2019, vol. 10, issue 1, 1-17

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-018-08247-x

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