Distinct Regulatory Programs Control the Latent Regenerative Potential of Dermal Fibroblasts during Wound Healing

Cell Stem Cell. 2020 Sep 3;27(3):396-412.e6. doi: 10.1016/j.stem.2020.07.008. | PubMed

Sepideh Abbasi¹, Sarthak Sinha¹, Elodie Labit¹, Nicole L Rosin¹, Grace Yoon¹, Waleed Rahmani¹, Arzina Jaffer¹, Nilesh Sharma¹, Andrew Hagner¹, Prajay Shah¹, Rohit Arora¹, Jessica Yoon¹, Anowara Islam¹, Aya Uchida¹, Chih Kai Chang², Jo Anne Stratton¹, R Wilder Scott², Fabio M V Rossi², T Michael Underhill², Jeff Biernaskie³

1. Department of Comparative Biology and Experimental Medicine, Faculty of Veterinary Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada.
2. Biomedical Research Centre, University of British Columbia, Vancouver, BC, Canada.
3. Department of Comparative Biology and Experimental Medicine, Faculty of Veterinary Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada; Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB T2N 4N1, Canada; Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada. Electronic address: jeff.biernaskie@ucalgary.ca.

Abstract

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.

Presented By Sarthak Sinha