의생명시스템학부

제목: Loss of Endothelial-derived Thrombospondin-1 Promotes Pulmonary Fibrosis

내용:

Pulmonary fibrosis is a chronic, progressive lung disease characterized by loss of alveolar epithelial cells and excessive deposition of extracellular matrix (ECM) destroying lung function. Studies have examined crosstalk between injured alveolar epithelial cells triggering fibroblast activation and have also shown that an increase in fibroblasts during pulmonary fibrosis may be due in part to epithelial-mesenchymal-transition (EMT). Lung endothelial cells (ECs) have been implicated in pulmonary fibrosis, yet their role during disease progression is poorly understood. Here we show that EC derived-thrombospondin-1 (TSP1) is critical for maintaining EC homeostasis and that bleomycin-induced lung damage downregulates EC TSP1 expression promoting EC hyperactivation and the acquisition of a mesenchymal phenotype by alveolar type I cells (AT1) in both human and mouse lung organoids. We find that hyperactivated TSP1-low ECs upregulates matrix metalloprotease (MMP) 3 which interacts with the cell surface receptor CD44 on AT1 cells promoting CD44 isoform switching and a mesenchymal transition thus increasing collagen production and driving pulmonary fibrosis. Although AT1 cells are thought to be terminally differentiated, generation of human AT1 lung organoids followed by exposure to bleomycin revealed the acquisition of a mesenchymal phenotype and increased collagen expression. Notably, bleomycin treatment of AT1 organoids in the presence of an MMP3 inhibitor or neutralizing antibody significantly attenuated collagen production. Our studies also show that TSP1-low ECs prevents AT2 differentiation into AT1 cells in human lung organoids indicating a key role for TSP1 in regulating the AT1 population in the lung. Collectively, our data demonstrate a critical role for lung ECs in pulmonary fibrosis and suggest that targeting TSP1, MMP3 or CD44 may offer new therapeutic approaches for this disease.