1493 Dynamic changes in fibroblast subpopulations drives development of radiation-induced skin fibrosis through the fra/c-jun pathway

Radiation induced skin fibrosis (RIF) is a debilitating sequela of radiation therapy, however the basic cellular pathophysiology driving this fibrotic development remains poorly defined. Clinically, fat grafting has been shown to improve fibrosis, but its mechanism unknown. We aimed delineate dynamics and associated pathways in RIF evaluate how these change with grafting-associated recovery irradiated skin. C57BL/6J ActinCre/ROSA26VT2/GK3 mice received 30Gy dorsal treatment fractionated doses was harvested at weeks 0, 2, 4, 8 following completion radiation. Fibrosis had temporal response from week 0 progressive increases dermal thickness collagen density along changes extracellular matrix organization loss vascularity. Tissue-resident cells expanded clonally injury. Single cell RNA sequencing revealed five transcriptionally distinct fibroblast subpopulations, three which increased prevalence concert fibrosis. Pathway analysis identified Fra/c-Jun signaling presence all subpopulations. Administration c-Jun inhibitor T-5224 prior mitigated subsequent Finally, chronic, radiation-injured reduced fibroblasts subpopulations characterized by promoted reduction These findings create an atlas for during mice. Furthermore, identification pathway involvement mirrors reports expression excisional wounding, ability limit therapy inhibition underscores potential common themes underlying pathogenesis both hypertrophic scarring RIF.