Transforming growth factor-β1 induces an epithelial-to-mesenchymal transition state in mouse hepatocytes in vitro
Transforming growth factor-β1 induces an epithelial-to-mesenchymal transition state in mouse hepatocytes in vitro
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DOI：
10.1074/jbc.m700998200
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发表时间：
2007-07-27
影响因子：
4.8
通讯作者：
Koteish, Ayman
中科院分区：
文献类型：
--
作者：
Kaimori, Aki;Potter, James;Koteish, Ayman
肝纤维化是一个渐进的病理过程，涉及过量的细胞外基质沉积，导致结构扭曲，最终导致肝硬化。转化生长因子-β（TGF-β）作为通过激活肝星状细胞以及其他成纤维细胞群体而在肝纤维化的发展和进展中的关键分子的作用是没有争议的。我们在此证明，TGF-β 1在体外诱导成熟肝细胞的上皮-间充质转化（EMT）状态。EMT状态的标志是α（1）（I）胶原mRNA表达的显著上调和I型胶原沉积。在“正常”小鼠肝细胞系（AML 12）中发现了类似的变化，从而证实肝细胞能够发生EMT变化和I型胶原合成。我们还发现，在EMT状态的肝细胞中，TGF-β 1诱导snail-1转录因子并激活Smad 2/3通路。TGF-β 1/Smad通路的核心作用的证据进一步得到了使用小干扰RNA技术通过Smad 4沉默抑制EMT的支持。总之，TGF-β 1是成熟肝细胞中已知的促凋亡细胞因子，能够介导表型变化和EMT形式的可塑性，导致胶原沉积。我们的研究结果支持EMT在肝纤维化的发展和进展中的潜在关键作用。
Liver fibrosis is a progressive pathologic process that involves deposition of excess extracellular matrix leading to distorted architecture and culminating in cirrhosis. The role of transforming growth factor-beta (TGF-beta) as a key molecule in the development and progression of hepatic fibrosis via the activation of hepatic stellate cells, among other fibroblast populations, is without controversy. We hereby show that TGF-beta 1 induces an epithelial-to-mesenchymal transition (EMT) state in mature hepatocytes in vitro. EMT state was marked by significant up-regulation of alpha(1) (I) collagen mRNA expression and type I collagen deposition. Similar changes were found in a " normal" mouse hepatocyte cell line (AML12), thus confirming that hepatocytes are capable of EMT changes and type I collagen synthesis. We also show that in hepatocytes in the EMT state, TGF-beta 1 induces the snail-1 transcription factor and activates the Smad2/3 pathway. Evidence for a central role of the TGF-beta 1/Smad pathway is further supported by the inhibition of EMT by Smad4 silencing using small interference RNA technology. In conclusion, TGF-beta 1, a known pro-apoptotic cytokine in mature hepatocytes, is capable of mediating phenotypic changes and plasticity in the form of EMT, resulting in collagen deposition. Our findings support a potentially crucial role for EMT in the development and progression of hepatic fibrogenesis.