Prrx1 Labels The Fibrogenic Fibroblast In The Ventral Dermis
Michael Hu, Tripp Leavitt, Julia Garcia, Ryan Ransom, Ulrike Litzenburger, Graham Walmsley, Clement Marshall, Alessandra Moore, Shamik Mascharak, Charles Chan, Derrick Wan, Peter Lorenz, Howard Chang, Michael Longaker
Stanford University, Stanford, CA, USA
BACKGROUND - Scarring and fibrosis lead to excessive morbidity and mortality, as well as countless lost healthcare dollars. Despite the lack of effective therapies, there is a $12 billion annual market for the treatment of scarring in the United States alone. Herein, we identify and characterize the fibroblast sub-population responsible for scarring in the mouse ventral dermis.
METHODS - Fibroblasts with embryonic expression of Prrx1 were lineage traced by crossing Prrx1Cre and ROSA26mTmG mice. Prrx1-positive fibroblasts (PPFs) and Prrx1-negative fibroblasts (PNFs) were characterized using flow cytometry, histology, and ATAC-seq analysis at various stages of embryonic development. PPFs were ablated using triple transgenic mice expressing Cre-dependent simian diphtheria toxin receptor (DTR). Histology with picrosirius red and tensile strength testing of fully healed wounds were performed. A novel method for automated quantification of collagen fiber characteristics was performed.
RESULTS - A sub-population of fibroblasts, labeled by the embryonic expression of Prrx1, was the key contributor to connective tissue deposition during scar formation in the ventral dermis. This lineage increased as a proportion of total fibroblasts within the ventral dermis over the course of gestation, associated with the transition from scarless to scarring repair. Differential patterns of chromosomal accessibility further demonstrated the heterogeneic nature of fibroblasts. Ablation of PPFs resulted in diminished connective tissue deposition when examined after completion of wound healing (*p<0.05) without change in the tensile strength of the scar (p>0.05). PPF ablation prior to transplantation of melanoma tumor xenografts resulted in decreased tumor mass (*p<0.05). Analysis of collagen fiber characteristics demonstrated significant differences after PPF ablation versus control (*p<0.05).
CONCLUSIONS - Prrx1 identifies the fibroblast sub-population with fibrogenic potential in the ventral dermis. Selectively ablating this fibroblast sub-population leads to decreased cutaneous scarring. Further research into the role of PPFs holds promise for novel therapeutics to decrease scarring and fibrosis.
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