Trajectory modeling of endothelial-to-mesenchymal transition reveals galectin-3 as a mediator in pulmonary fibrosis.
Trajectory modeling of endothelial-to-mesenchymal transition reveals galectin-3 as a mediator in pulmonary fibrosis.
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DOI：
10.1038/s41419-021-03603-0
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发表时间：
2021-03-26
影响因子：
9
通讯作者：
Wu Q
中科院分区：
文献类型：
--
作者：
Jia W;Wang Z;Gao C;Wu J;Wu Q
内皮-间质转化（EndMT）是特发性肺纤维化（IPF）中纤维化细胞的重要来源。然而，内皮细胞（EC）如何被激活以及EndMT如何影响IPF在很大程度上仍然是难以捉摸的。在这里，我们使用无监督的伪时间分析来识别EC的异质性，并重建博莱霉素（BLM）处理的Tie 2creER/+; Rosa 26 tdTomato/+ IPF小鼠的EndMT轨迹。像C3 ar 1和Lgals 3（蛋白质名称galectin-3）这样的基因与过渡性假时间高度相关，其表达在纤维化中EC从静止到激活的命运转换期间逐渐上调。通过siRNA或蛋白拮抗剂抑制小鼠Galectin-3可减轻IPF的发病机制和EC的转化。半乳糖凝集素-3（galectin-3，GSK 3）基因的重组蛋白和/或siRNA在体外刺激人肺微血管内皮细胞（human pulmonary microvascular endothelial cell，HPMECs）后，β-catenin/GSK 3 β信号通路及其上游调控因子AKT受到干扰，提示它们介导了EndMT的进展。这些结果表明EndMT在IPF过程中至关重要，并为血管重塑提供了潜在的治疗靶点。
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 Tie2creER/+;Rosa26tdTomato/+ 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.
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