The Hedgehog System Machinery Controls Transforming Growth Factor-β-Dependent Myofibroblastic Differentiation in Humans Involvement in Idiopathic Pulmonary Fibrosis
The Hedgehog System Machinery Controls Transforming Growth Factor-β-Dependent Myofibroblastic Differentiation in Humans Involvement in Idiopathic Pulmonary Fibrosis
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DOI：
10.1016/j.ajpath.2012.08.019
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发表时间：
2012-12-01
影响因子：
6
通讯作者：
Mailleux, Arnaud A.
中科院分区：
文献类型：
--
作者：
Cigna, Natacha;Moshai, Elika Farrokhi;Mailleux, Arnaud A.
特发性肺纤维化（IPF）是一种原因不明的破坏性疾病。关键信号发育途径在IPF中异常表达。Hedgehog通路在胎肺发育过程中起关键作用，并可能参与肺纤维化。我们确定了正常和IPF人肺活检和原代成纤维细胞中几种Sonic hedgehog（SHH）途径成员的表达模式。hedgehog通路抑制的效果通过在有和没有转化生长因子（TGF）-β 1的情况下肺成纤维细胞增殖和分化来测定。我们发现hedgehog通路在IPF肺中重新激活。重要的是，我们破译了人肺成纤维细胞中hedgehog和TGF-β通路之间的串扰。TGF-β 1调节hedgehog通路的关键组分的表达，而不依赖于该通路的强制性信号转导子Smoothened。Smoothened是TGF-β 1诱导的对照成纤维细胞的肌纤维母细胞分化所必需的，但IPF成纤维细胞的分化对Smoothened抑制部分耐受。此外，在肌纤维母细胞分化期间，TGF-β 1对正常和IPF成纤维细胞的作用需要来自初级纤毛的功能性hedgehog途径机制以及细胞核中的GLI依赖性转录。这些数据确定了GLI转录因子作为肺纤维化的潜在治疗靶点。(Am J Pathol 2012，181：2126-2137; http：//dx·doi·org/10·1016/j·ajpath·2012·08·019）
Idiopathic pulmonary fibrosis (IPF) is a devastating disease of unknown cause. Key signaling developmental pathways are aberrantly expressed in IPF. The hedgehog pathway plays a key role during fetal lung development and may be involved in lung fibrogenesis. We determined the expression pattern of several Sonic hedgehog (SHH) pathway members in normal and IPF human lung biopsies and primary fibroblasts. The effect of hedgehog pathway inhibition was assayed by lung fibroblast proliferation and differentiation with and without transforming growth factor (TGF)-beta 1. We showed that the hedgehog pathway was reactivated in the IPF lung. Importantly, we deciphered the cross talk between the hedgehog and TGF-beta pathway in human lung fibroblasts. TGF-beta 1 modulated the expression of key components of the hedgehog pathway independent of Smoothened, the obligatory signal transducer of the pathway. Smoothened was required for TGF-beta 1 induced myofibroblastic differentiation of control fibroblasts, but differentiation of IPF fibroblasts was partially resistant to Smoothened inhibition. Furthermore, functional hedgehog pathway machinery from the primary cilium, as well as GLI-dependent transcription in the nucleus, was required for the TGF-beta 1 effects on normal and IPF fibroblasts during myofibroblastic differentiation. These data identify the GLI transcription factors as potential therapeutic targets in lung fibrosis. (Am J Pathol 2012, 181:2126-2137; http://dx.doi.org/10.1016/j.ajpath.2012.08.019)