TGFβ drives fibrotic remodeling via modulation of homeostatic and pathological fibroblast populations in a murine model of pulmonary fibrosis

Idiopathic Pulmonary Fibrosis (IPF) is a chronic parenchymal lung disease marked by myofibroblast proliferation and excess matrix deposition. Recent characterization of IPF lungs and multiple murine models by ScRNA sequencing identified 2 disease-associated mesenchymal subsets, <italic>Cthrc1</italic>+ collagen producing cells and an “inflammatory-transitional” population derived from homeostatic alveolar or adventitial populations. Using our Surfactant Protein C (<italic>Sftpc^I73T</italic>) conditional knock-in model of lung fibrosis, we recently showed that TGFβ activates both homeostatic and transitional populations to enter a fibrotic state. The goal of this study was to further define function and dynamics of the transitional subset during aberrant lung remodeling. Tamoxifen administration to <italic>Sftpc^I73T</italic> mice induces expression of mutant protein and promotes an inflammatory cascade followed by fibrogenesis. In an <italic>ex vivo</italic> organoid assay, transitional populations isolated from the model and cultured with <italic>Sftpc^I73T</italic> AT2 cells were superior to either alveolar, adventitial, or <italic>Cthrc1</italic> subsets in promoting colony forming efficiency and size. <italic>In vivo</italic>, administration of a TGFβ signaling inhibitor (SB-525334 30mg/kg twice daily) beginning early in fibrogenesis ameliorated weight loss, increased survival, decreased collagen deposition, and preserved lung physiology. By flow cytometry, SB-525334 preserved homeostatic and transitional fibroblast populations while decreasing <italic>Cthrc1+</italic> cells. These data reinforce a fundamental role for TGFβ signaling in lung fibrogenesis whose inhibition may preserve pro-reparative fibroblast subsets while preventing emergence of pathological fibroblasts.