Inhibition of Wnt/β-catenin signaling suppresses myofibroblast differentiation of lung resident mesenchymal stem cells and pulmonary fibrosis
Inhibition of Wnt/β-catenin signaling suppresses myofibroblast differentiation of lung resident mesenchymal stem cells and pulmonary fibrosis
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抑制 Wnt/β-连环蛋白信号传导抑制肺驻留间充质干细胞的肌成纤维细胞分化和肺纤维化
DOI：
10.1038/s41598-018-28968-9
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发表时间：
2018-09-11
影响因子：
4.6
通讯作者：
Han, Xiaodong
中科院分区：
文献类型：
--
作者：
Cao, Honghui;Wang, Cong;Han, Xiaodong
一个新兴的范例提出了肺驻留间充质干细胞（LR-MSCs）通过成纤维细胞转分化事件在特发性肺纤维化（IPF）发病机制中的关键作用。Wnt/β-连环蛋白信号传导的异常激活发生在几乎所有的纤维化肺疾病中，并且与间充质干细胞（MSC）的分化相关。在体外，通过测量参与Wnt/β-连环蛋白信号传导的几个关键组分的蛋白水平，我们证实了该信号传导途径在LR-MSCs的肌成纤维细胞分化中被激活。通过小分子ICG-001靶向抑制Wnt/β-连环蛋白信号传导，剂量依赖性地阻碍了LR-MSC的增殖和转化生长因子-β 1（TGF-β 1）介导的纤维化作用。在体内，博来霉素处理后，ICG-001通过阻断间充质-肌成纤维细胞转化、抑制基质基因表达和减少细胞凋亡发挥其肺保护作用。此外，延迟给予ICG-001可减轻博来霉素诱导的肺纤维化，这可能是一种有希望的IPF干预治疗策略。有趣的是，ICG-001的这些抗纤维化作用是通过一种独立于Smad激活的任何破坏的机制来操作的。总之，我们的研究表明，Wnt/β-catenin信号转导可能是一个重要的机制，潜在的调节LR-MSCs的肌成纤维细胞分化和他们进一步参与肺纤维化的发展。
An emerging paradigm proposes a crucial role for lung resident mesenchymal stem cells (LR-MSCs) via a fibroblastic transdifferentiation event in the pathogenesis of idiopathic pulmonary fibrosis (IPF). Aberrant activation of Wnt/beta-catenin signaling occurs in virtually all fibrotic lung diseases and is relevant to the differentiation of mesenchymal stem cells (MSCs). In vitro, by measuring the protein levels of several key components involved in Wnt/beta-catenin signaling, we confirmed that this signaling pathway was activated in the myofibroblast differentiation of LR-MSCs. Targeted inhibition of Wnt/beta-catenin signaling by a small molecule, ICG-001, dose-dependently impeded the proliferation and transforming growth factor-beta 1 (TGF-beta 1)-mediated fibrogenic actions of LR-MSCs. In vivo, ICG-001 exerted its lung protective effects after bleomycin treatment through blocking mesenchymal-myofibroblast transition, repressing matrix gene expression, and reducing cell apoptosis. Moreover, delayed administration of ICG-001 attenuated bleomycin-induced lung fibrosis, which may present a promising therapeutic strategy for intervention of IPF. Interestingly, these antifibrotic actions of ICG-001 are operated by a mechanism independent of any disruption of Smad activation. In conclusion, our study demonstrated that Wnt/beta-catenin signaling may be an essential mechanism underlying the regulation of myofibroblast differentiation of LR-MSCs and their further participation in the development of pulmonary fibrosis.