Fibroblast-specific Stat1 deletion enhances the myofibroblast phenotype during tissue repair

Abstract

Signal transducer and activator of transcription 1 (Stat1) is a ubiquitously expressed latent transcription factor that is activated by many cytokines and growth factors. Global Stat1 knockout mice are prone to chemical-induced lung and liver fibrosis, suggesting roles for Stat1 in tissue repair. However, the importance of Stat1 in fibroblast-mediated and vascular smooth muscle cell (VSMC)-mediated injury response has not been directly evaluated in vivo. Here, we focused on two models of tissue repair in conditional Stat1 knockout mice: excisional skin wounding in mice with Stat1 deletion in dermal fibroblasts, and carotid artery ligation in mice with global Stat1 deletion or deletion specific to VSMCs. In the skin model, dermal wounds closed at a similar rate in mice with fibroblast Stat1 deletion and controls, but collagen and α-smooth muscle actin (αSMA) expression were increased in the mutant granulation tissue. Cultured Stat1 ^-/- and Stat1 ^+/- dermal fibroblasts exhibited similar αSMA⁺ stress fiber assembly, collagen gel contraction, proliferation, migration, and growth factor-induced gene expression. In the artery ligation model, there was a significant increase in fibroblast-driven perivascular fibrosis when Stat1 was deleted globally. However, VSMC-driven remodeling and neointima formation were unchanged when Stat1 was deleted specifically in VSMCs. These results suggest an in vivo role for Stat1 as a suppressor of fibroblast mediated, but not VSMC mediated, injury responses, and a suppressor of the myofibroblast phenotype.