Trajectory modeling of endothelial-to-mesenchymal transition reveals galectin-3 as a mediator in pulmonary fibrosis

• Published in: Cell death & disease Vol. 12; no. 4; p. 327
• Main Authors: Jia, Wangyue, Wang, Zhaoyan, Gao, Ceshu, Wu, Jian, Wu, Qiong
• Format: Journal Article
• Language: English
• Published: England Springer Nature B.V 26.03.2021; Nature Publishing Group UK; Nature Publishing Group
• Subjects: AKT protein; Antagonists; Bleomycin; Endothelial cells; Fibrosis; Galectin-3; Lung diseases; Mesenchyme; Microvasculature; Pulmonary fibrosis; siRNA; β-Catenin
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-021-03603-0

The endothelial-to-mesenchymal transition (EndMT) is an important source of fibrotic cells in idiopathic pulmonary fibrosis (IPF). However, how endothelial cells (ECs) are activated and how EndMT impact IPF remain largely elusive. Here, we use unsupervised pseudotemporal analysis to recognize the heterogeneity of ECs and reconstruct EndMT trajectory of bleomycin (BLM)-treated Tie2 ;Rosa26 IPF mice. Genes like C3ar1 and Lgals3 (protein name galectin-3) are highly correlated with the transitional pseudotime, whose expression is gradually upregulated during the fate switch of ECs from quiescence to activation in fibrosis. Inhibition of galectin-3 via siRNA or protein antagonists in mice could alleviate the pathogenesis of IPF and the transition of ECs. With the stimulation of human pulmonary microvascular endothelial cells (HPMECs) by recombinant proteins and/or siRNAs for galectin-3 in vitro, β-catenin/GSK3β signaling and its upstream regulator AKT are perturbed, which indicates they mediate the EndMT progress. These results suggest that EndMT is essential to IPF process and provide potential therapeutic targets for vascular remodeling.