期刊
CELL STEM CELL
卷 27, 期 3, 页码 396-+出版社
CELL PRESS
DOI: 10.1016/j.stem.2020.07.008
关键词
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资金
- Canadian Institutes of Health Research [MOP-106646, PJT-401394, PJT-148816, FDN-159908]
- Calgary Firefighters Burn Treatment Society
- UCVM Dean's Excellence Award
- CIHR Vanier doctoral scholarship
- Alberta Innovates (AI) doctoral scholarship
- Killam doctoral scholarship
- Alberta Children's Hospital Research Institute postdoctoral fellowships
- AI MD/PhD scholarship
- CIHR master's scholarship
Dermal fibroblasts exhibit considerable heterogeneity during homeostasis and in response to injury. Defining lineage origins of reparative fibroblasts and regulatory programs that drive fibrosis or, conversely, promote regeneration will be essential for improving healing outcomes. Using complementary fate-mapping approaches, we show that hair follicle mesenchymal progenitors make limited contributions to wound repair. In contrast, extrafollicular progenitors marked by the quiescence-associated factor Hic1 generated the bulk of reparative fibroblasts and exhibited functional divergence, mediating regeneration in the center of the wound neodermis and scar formation in the periphery. Single-cell RNA-seq revealed unique transcriptional, regulatory, and epithelial-mesenchymal crosstalk signatures that enabled mesenchymal competence for regeneration. Integration with scATAC-seq highlighted changes in chromatin accessibility within regeneration-associated loci. Finally, pharmacological modulation of RUNX1 and retinoic acid signaling or genetic deletion of Hic1 within wound-activated fibroblasts was sufficient to modulate healing outcomes, suggesting that reparative fibroblasts have latent but modifiable regenerative capacity.
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