Identification of novel mechanisms in pulmonary fibrosisNotch3-Jag1/2 signaling mediating epithelial stem cell and fibroblast interaction is essential in lung fibrogenesis and emerges as a potential therapeutic strategy for IPF

Abstract

Our investigation identifies the axis Notch3-Jag1/2 mediating epithelial-stromal cell communication in lung fibrogenesis. We have demonstrated that Notch3 deficiency or the inhibition of AT2-derived Jag1/2 attenuates the development of fibrosis, reducing the deposit of collagen and decreasing the differentiation of αSMA myofibroblasts impeding lung function decline in animal models. Thus, our work discovers Notch3-Jag1/2 signaling as a previously unrecognized mechanism involved in the development of pulmonary fibrosis. These findings are highly relevant because 1) identify novel subsets of mesenchymal cells and AT2 cells that behave as profibrotic activating Notch signaling through the Notch ligands Jag1 and Jag2 and reveal the participation of lung stem cells in the fibrotic process, and 2) unveil potential new therapeutic targets for the treatment of human IPF.