Dermal fibroblast expression of transcriptional co-factors YAP/TAZ regulates dermal extracellular matrix homeostasis and fibrotic scar formation in mouse skin

Summary: Abstract Body: The collagen-rich dermal extracellular matrix (ECM) provides both mechanical support and a microenvironment crucial for the functions of dermal cells. Dermal fibroblasts play an essential role in this process. We have investigated the function of two homologous transcriptional co-factors, YAP and TAZ, in dermal ECM homeostasis utilizing conditional Cre-LoxP deletion to eliminate YAP/TAZ expression in dermal fibroblasts. We report that deleting YAP/TAZ in dermal fibroblasts three days after birth leads to marked reductions in dermal collagen fibril production, ECM deposition, and ECM organization. The density of the dermal collagen and gene expression of type I collagen were significantly diminished, with reductions of 67% (p<0.035) and 88% (p<0.001), respectively. Spatial RNA sequencing of the dermis revealed a substantial decrease in the expression of the major collagen genes such as COL1A1 (76% reduction, p<0.0001), COL1A2 (73% reduction, p<0.0001), COL3A1 (58% reduction, p<0.0004), and a negative enrichment of the YAP/TAZ signaling pathway. Further investigations into fibrotic scarring following incisional tail wounding demonstrated that scar formation, measured 4, 8, and 12 weeks after wounding, was significantly attenuated in YAP/TAZ knockout mice. Dermal thickness was reduced by 50% (p>0.01) 12 weeks post wounding, compared to age and sex-matched littermate controls. Similarly, in models of bleomycin-induced skin fibrosis, the fibrotic response was significantly reduced (33% reduction, p<0.01)in YAP/TAZ knockout mice. These results highlight the critical involvement of YAP/TAZ in fibroblasts in regulating dermal ECM homeostasis and fibrotic scar formation and identify targeting the YAP/TAZ signaling pathway in fibroblasts as a promising approach for ameliorating fibrotic scarring. Gary J. Fisher¹, Zhaoping Qin¹, Alexandre Ermilov¹, Ava J. Kim¹, Junyoung Kim¹, John J. Voorhees¹, Taihao Quan¹ 1. Department of Dermatology, University of Michigan, Ann Arbor, MI, United States. Cell Communication Networks and Stromal Biology