Hepatocytes do not undergo epithelial-mesenchymal transition in liver fibrosis in mice.
Hepatocytes do not undergo epithelial-mesenchymal transition in liver fibrosis in mice.
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DOI：
10.1002/hep.23368
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发表时间：
2010-03
期刊：
影响因子：
13.5
通讯作者：
Brenner, David A.
中科院分区：
文献类型：
--
作者：
Taura, Kojiro;Miura, Kouichi;Iwaisako, Keiko;Osterreicher, Christoph H.;Kodama, Yuzo;Penz-Osterreicher, Melitta;Brenner, David A.
肝纤维化中纤维化细胞的起源仍有争议。我们评估了肝细胞通过上皮-间质转化（EMT）促进肝纤维化细胞外基质（ECM）产生的新概念。我们培育了表达ROSA 26 stop β-gal、白蛋白Cre、胶原蛋白α1（I）GFP的三重转基因小鼠，其中肝细胞来源的细胞被β-半乳糖苷酶（β-gal）永久标记，I型胶原蛋白表达细胞被GFP标记。我们通过重复注射四氯化碳（CCl 4）诱导肝纤维化。评价肝切片和分离的细胞的GFP和β-gal以及α-平滑肌肌动蛋白（α-SMA）和成纤维细胞特异性蛋白1（FSP-1）的表达。在用TGFβ-1刺激后，从未处理的肝脏分离的培养肝细胞表达GFP和β-gal，具有成纤维细胞样形态学变化，但缺乏其他间充质标志物的表达。来自CCl 4处理的肝脏的细胞从未显示GFP和β-gal的双重阳性。所有β-gal阳性细胞均显示丰富的胞浆，具有典型的肝细胞形态，不表达间充质标志物，包括α-SMA、FSP-1、结蛋白和波形蛋白。在CCl 4处理的小鼠的肝切片中，GFP阳性区域与纤维化间隔一致，并且从不重叠X-gal阳性区域。结论：I型胶原生成细胞并非来源于肝细胞。体内肝细胞既不获得间充质标志物表达，也不表现出与正常肝细胞明显不同的形态学变化。我们的研究结果强烈挑战了肝细胞在体内通过EMT获得间充质表型以在肝纤维化中产生ECM的概念。
The origin of fibrogenic cells in liver fibrosis remains controversial. We assessed the emerging concept that hepatocytes contribute to production of extracellular matrix (ECM) in liver fibrosis through epithelial-mesenchymal transition (EMT). We bred triple transgenic mice expressing ROSA26 stop β-gal; Albumin Cre; Collagen α1(I) GFP, in which hepatocyte-derived cells are permanently labeled by β-galactosidase (β-gal) and type I collagen-expressing cells are labeled by GFP. We induced liver fibrosis by repetitive carbon tetrachloride (CCl4) injections. Liver sections and isolated cells were evaluated for GFP and β-gal as well as expression of α-smooth muscle actin (α-SMA) and fibroblast specific protein 1 (FSP-1). Upon stimulation with TGFβ-1, cultured hepatocytes isolated from untreated liver expressed both GFP and β-gal with a fibroblast-like morphological change but lacked expression of other mesenchymal markers. Cells from CCl4-treated livers never showed double-positivity for GFP and β-gal. All β-gal positive cells exhibited abundant cytoplasm, a typical morphology of hepatocytes and expressed none of mesenchymal markers including α-SMA, FSP-1, desmin, and vimentin. In liver sections of CCl4-treated mice, GFP-positive areas were coincident with fibrotic septa and never overlapped X-gal-positive areas. Conclusion: Type I collagen-producing cells do not originate from hepatocytes. Hepatocytes in vivo neither acquire mesenchymal marker expression, nor exhibit a morphological change clearly distinguishable from normal hepatocytes. Our results strongly challenge the concept that hepatocytes in vivo acquire a mesenchymal phenotype through EMT to produce the ECM in liver fibrosis.
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影响因子：
15.9
作者：
Omenetti, Alessia;Porrello, Alessandro;Diehl, Anna Mae
通讯作者：
Diehl, Anna Mae
影响因子：
29.4
作者：
Dooley, Steven;Hamzavi, Jafar;Mertens, Peter R.
通讯作者：
Mertens, Peter R.
影响因子：
4.8
作者：
Osawa, Y;Uchinami, H;Brenner, DA
通讯作者：
Brenner, DA
DOI：
10.1513/pats.200601-004tk
发表时间：
2006-06-01
期刊：
Proceedings of the American Thoracic Society
影响因子：
--
作者：
Willis, Brigham C;duBois, Roland M;Borok, Zea
通讯作者：
Borok, Zea
DOI：
10.1073/pnas.96.9.5037
发表时间：
1999-04-27
影响因子：
11.1
作者：
Mao, XH;Fujiwara, Y;Orkin, SH
通讯作者：
Orkin, SH