Negative regulation of myofibroblast differentiation by PTEN (phosphatase and tensin homolog deleted on chromosome 10)
Negative regulation of myofibroblast differentiation by PTEN (phosphatase and tensin homolog deleted on chromosome 10)
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DOI：
10.1164/rccm.200507-1058oc
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发表时间：
2006-01-01
影响因子：
24.7
通讯作者：
Toews, GB
中科院分区：
文献类型：
--
作者：
White, ES;Atrasz, RG;Toews, GB
原理：肌成纤维细胞是特发性肺纤维化（IPF）的主要效应细胞。明确肌成纤维细胞分化的机制对于开发新型治疗药物可能是至关重要的。目的：证明在体内肌成纤维细胞分化受10号染色体缺失的磷酸酶和张力蛋白同源物（phosphatase and tensin homolog deleted on chromosome 10，PTEN）活性的调节，并确定发生这种情况的潜在机制。我们使用IPF患者手术肺活检的组织切片来定位PTEN和α-平滑肌肌动蛋白（α-SMA）的表达。我们使用细胞培养的pten（-/-）和野生型成纤维细胞，以及腺病毒策略和药理学抑制剂，以确定的机制，其中PTEN抑制α-SMA，成纤维细胞增殖，和胶原production.Results：在人类肺标本的IPF，成纤维细胞病灶内的肌成纤维细胞表现出减少PTEN的表达。此外，在小鼠中抑制PTEN使博莱霉素诱导的纤维化恶化。在pten（-/-）成纤维细胞和PTEN受到抑制的正常成纤维细胞中，α-SMA、增殖和胶原蛋白的产生上调。在野生型细胞中加入转化生长因子-β，而不是pten（-/-）细胞，导致α-SMA表达以时间依赖性方式增加。在pten（-/-）细胞中，PTEN的重建降低了α-SMA的表达、增殖和胶原蛋白的产生，而在野生型细胞中PTEN的过表达抑制了转化生长因子β诱导的肌成纤维细胞分化。据观察，蛋白质和脂质磷酸酶作用的PTEN能够调节肌成纤维细胞phenotype.Conclusions：结果表明，在IPF，肌成纤维细胞有减少PTEN的表达。体内抑制PTEN促进纤维化，体外抑制成肌纤维细胞分化。
Rationale: Myofibroblasts are primary effector cells in idiopathic pulmonary fibrosis (IPF). Defining mechanisms of myofibroblast differentiation may be critical to the development of novel therapeutic agents.Objective: To show that myofibroblast differentiation is regulated by phosphatase and tensin homolog deleted on chromosome 10 (PTEN) activity in vivo, and to identify a potential mechanism by which this occurs.Methods: We used tissue sections of surgical lung biopsies from patients with IPF to localize expression of PTEN and alpha-smooth muscle actin (alpha-SMA). We used cell culture of pten(-/-) and wildtype fibroblasts, as well as adenoviral strategies and pharmacologic inhibitors, to determine the mechanism by which PTEN inhibits alpha-SMA, fibroblast proliferation, and Collagen production.Results: In human lung specimens of IPF, myofibroblasts within fibroblastic foci demonstrated diminished PTEN expression. Furthermore, inhibition of PTEN in mice worsened bleomycin-induced fibrosis. In pten(-/-) fibroblasts, and in normal fibroblasts in which PTEN was inhibited, alpha-SMA, proliferation, and Collagen production was upregulated. Addition of transforming growth factor-beta to wildtype cells, but not pten(-/-) cells, resulted in increased alpha-SMA expression in a time-dependent fashion. In pten(-/-) cells, reconstitution of PTEN decreased alpha-SMA expression, proliferation, and Collagen production, whereas overexpression of PTEN in wild-type cells inhibited transforming growth factor-beta-induced myofibroblast differentiation. It was observed that both the protein and lipid phosphatase actions of PTEN were capable of modulating the myofibroblast phenotype.Conclusions: The results indicate that in IPF, myofibroblasts have diminished PTEN expression. Inhibition of PTEN in vivo promotes fibrosis, and PTEN inhibits myofibroblast differentiation in vitro.