Calponin 1 contributes to myofibroblast differentiation of human pleural mesothelial cells
Calponin 1 contributes to myofibroblast differentiation of human pleural mesothelial cells
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DOI：
10.1152/ajplung.00289.2021
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发表时间：
2022-03-01
影响因子：
4.9
通讯作者：
Ikebe, Mitsuo
中科院分区：
文献类型：
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作者：
Choo, Young-Yeon;Sakai, Tsuyoshi;Ikebe, Mitsuo
胸膜间皮细胞（PMCs）可以通过间皮-间充质转化（MesoMT）成为肌成纤维细胞，并有助于胸膜机化、纤维化和外皮形成。然而，这些转化的间皮细胞如何促进肺纤维化仍不清楚。在此，我们研究了PMC收缩性肌成纤维细胞分化的机制。转化生长因子-β（TGF-β）诱导钙调蛋白1表达显著上调，这与人PMC（HPMC）中显著的细胞骨架重排相关，以产生应力纤维。下调calponin 1表达可减少应激纤维的形成。有趣的是，诱导应力纤维主要含有与钙调蛋白1相关的α-平滑肌肌动蛋白（α SMA），而不是β-肌动蛋白。钙调蛋白1相关的应力纤维也含有肌球蛋白II和α-辅肌动蛋白。此外，局灶性粘连与产生的应力纤维对齐。这些结果表明，钙调蛋白1促进类似收缩肌原纤维的应力纤维的形成。支持这一观点的是，TGF-β显著增加了HPMC的收缩活性，这种作用可通过下调钙调蛋白1的表达而消除。我们推断，HPMCs分化为收缩性肌成纤维细胞有助于胸膜瘢痕组织的僵硬，从而促进胸膜纤维化（PF），并且钙调蛋白1的上调在此过程中起着核心作用。
Pleural mesothelial cells (PMCs) can become myofibroblasts via mesothelial-mesenchymal transition (MesoMT) and contribute to pleural organization, fibrosis, and rind formation. However, how these transformed mesothelial cells contribute to lung fibrosis remains unclear. Here, we investigated the mechanism of contractile myofibroblast differentiation of PMCs. Transforming growth factor -beta (TGF-beta) induced marked upregulation of calponin 1 expression, which was correlated with notable cytoskeletal rear-rangement in human PMCs (HPMCs) to produce stress fibers. Downregulation of calponin 1 expression reduced stress fiber for-mation. Interestingly, induced stress fibers predominantly contain alpha-smooth muscle actin (alpha SMA) associated with calponin 1 but not beta-actin. Calponin 1-associated stress fibers also contained myosin II and alpha-actinin. Furthermore, focal adhesions were aligned with the produced stress fibers. These results suggest that calponin 1 facilitates formation of stress fibers that resemble contract-ile myofibrils. Supporting this notion, TGF-beta significantly increased the contractile activity of HPMCs, an effect that was abolished by downregulation of calponin 1 expression. We infer that differentiation of HPMCs to contractile myofibroblasts facilitates stiff-ness of scar tissue in pleura to promote pleural fibrosis (PF) and that upregulation of calponin 1 plays a central role in this process.