Notch1 通过 PDGFR/ROCK1 信号通路促进特发性肺纤维化中的周细胞-肌成纤维细胞转化。,Experimental & Molecular Medicine

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Notch1 通过 PDGFR/ROCK1 信号通路促进特发性肺纤维化中的周细胞-肌成纤维细胞转化。
Experimental & Molecular Medicine ( IF 9.5 ) Pub Date : 2019-03-20 , DOI: 10.1038/s12276-019-0228-0
Yi-Chun Wang ₁ , Qiong Chen ₂ , Jun-Ming Luo ₂ , Jing Nie ₂ , Qing-He Meng ₃ , Wei Shuai ₂ , Han Xie ₂ , Jia-Mei Xia ₂ , Hui Wang ₄

Affiliation

本研究旨在探讨Notch1/PDGFRβ/ROCK1信号通路在肺纤维化发病机制中的作用，并探讨靶向Notch1治疗肺纤维化的可能性。使用 RT-qPCR、蛋白质印迹和免疫染色检查肺纤维化患者的肺组织中 Notch1/PDGFRβ/ROCK1 的表达。用 Notch1 过表达的载体或靶向 PDGFRβ/ROCK1 的 shRNA 转染培养的小鼠肺周细胞，以检查细胞行为，包括增殖、细胞周期停滞和向肌成纤维细胞的分化。最后制备小鼠肺纤维化模型，给予Notch1抑制剂观察组织形态和周细胞行为。人肺纤维化组织呈 Notch1、PDGFRβ 和 ROCK1 过表达，除了周细胞向肌成纤维细胞的显着转变。在培养的小鼠肺周细胞中，Notch1的过表达导致细胞增殖和分化加速，同时也增加了PDGFRβ和ROCK1蛋白的表达。周细胞中 PDGFRβ/ROCK1 的敲低显着抑制了周细胞的增殖和分化。作为进一步证实，在肺纤维化小鼠模型中施用 Notch1 抑制剂可抑制 PDGFRβ/ROCK1 通路，抑制周细胞增殖和分化，并减轻纤维化的严重程度。我们的研究结果表明，Notch1 信号通路在肺纤维化中异常激活，该通路可能通过介导周细胞增殖和分化促进疾病进展。

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Notch1 promotes the pericyte-myofibroblast transition in idiopathic pulmonary fibrosis through the PDGFR/ROCK1 signal pathway.

The goals of this study were to investigate the role of the Notch1/PDGFRβ/ROCK1 signaling pathway in the pathogenesis of pulmonary fibrosis and to explore the possibility of treating fibrosis by targeting Notch1. Lung tissues from patients with pulmonary fibrosis were examined for the expression of Notch1/PDGFRβ/ROCK1 using RT-qPCR, western blotting, and immunostaining. Cultured mouse lung pericytes were transfected with Notch1-overexpressed vectors or shRNA targeting PDGFRβ/ROCK1 to examine cell behaviors, including proliferation, cell cycle arrest, and differentiation toward myofibroblasts. Finally, a mouse pulmonary fibrosis model was prepared, and a Notch1 inhibitor was administered to observe tissue morphology and pericyte cell behaviors. Human pulmonary fibrotic tissues presented with overexpression of Notch1, PDGFRβ, and ROCK1, in addition to a prominent transition of pericytes into myofibroblasts. In cultured mouse lung pericytes, overexpression of Notch1 led to the accelerated proliferation and differentiation of cells, and it also increased the expression of the PDGFRβ and ROCK1 proteins. The knockdown of PDGFRβ/ROCK1 in pericytes remarkably suppressed pericyte proliferation and differentiation. As further substantiation, the administration of a Notch1 inhibitor in a mouse model of lung fibrosis inhibited the PDGFRβ/ROCK1 pathway, suppressed pericyte proliferation and differentiation, and alleviated the severity of fibrosis. Our results showed that the Notch1 signaling pathway was aberrantly activated in pulmonary fibrosis, and this pathway may facilitate disease progression via mediating pericyte proliferation and differentiation. The inhibition of the Notch1 pathway may provide one promising treatment strategy for pulmonary fibrosis.

更新日期：2019-05-16

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