Identification of adult hepatic progenitor cells capable of repopulating injured rat liver
Identification of adult hepatic progenitor cells capable of repopulating injured rat liver
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DOI：
10.1002/hep.22047
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发表时间：
2008-02-01
期刊：
影响因子：
13.5
通讯作者：
Dabeva, Mariana D.
中科院分区：
文献类型：
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作者：
Yovchev, Mladen I.;Grozdanov, Petar N.;Dabeva, Mariana D.
当肝细胞增殖受损时，卵圆细胞在肝脏中出现并扩增。许多不同的标志物已被归于这些细胞，但它们的性质仍然不明确。本研究是一项详细的基因表达分析，旨在揭示它们的身份以及在体内的再增殖能力。在接受2 - 乙酰氨基芴处理并进行部分肝切除的大鼠或接受D - 半乳糖胺处理的大鼠中，卵圆细胞被激活。两种表面标志物[上皮细胞黏附分子（EpCAM）和胸腺细胞抗原1（Thy - 1）]被用于纯化新鲜分离的细胞。利用Affymetrix大鼠表达阵列230 2.0、逆转录酶聚合酶链反应和免疫荧光显微镜对它们的基因表达进行了研究。我们发现EpCAM（+）和Thy - 1（+）细胞代表卵圆细胞微环境中的两种不同细胞群。EpCAM（+）细胞表达经典的卵圆细胞标志物（甲胎蛋白、细胞角蛋白 - 19、OV - 1抗原、α6整合素和连接蛋白43）、我们最近鉴定的细胞表面标志物（CD44、CD24、EpCAM、水通道蛋白5、紧密连接蛋白 - 4、促胰液素受体、紧密连接蛋白 - 7、V - ros肉瘤病毒癌基因同源物1、钙黏蛋白22、黏蛋白 - 1和CD133）以及肝脏富集转录因子（叉头框q、叉头框a2、单切1和转录因子2）。卵圆细胞不表达先前报道的造血干细胞标志物Thy - 1、c - kit和CD34或神经上皮标志物神经细胞黏附分子1。然而，卵圆细胞表达许多间充质标志物，包括波形蛋白、间皮素、骨形态发生蛋白7和Tweak受体（肿瘤坏死因子受体超家族，成员12A）。还介绍了一组新的差异表达的卵圆细胞基因。结果表明，Thy - 1（+）细胞是具有肌成纤维细胞/活化星状细胞特征的间充质细胞。移植实验显示，EpCAM（+）细胞是能够使受损大鼠肝脏再增殖的真正祖细胞。结论：我们已经表明，EpCAM（+）卵圆细胞是双潜能的成年肝上皮祖细胞。这些细胞表现出一种先前未被认识的混合上皮/间充质表型。它们是肝细胞治疗的有价值的候选细胞。
Oval cells appear and expand in the liver when hepatocyte proliferation is compromised. Many different markers have been attributed to these cells, but their nature still remains obscure. This study is a detailed gene expression analysis aimed at revealing their identity and repopulating in vivo capacity. Oval cells were activated in 2-acetylaminofluorene-treated rats subjected to partial hepatectomy or in D-galactosamine-treated rats. Two surface markers [epithelial cell adhesion molecule (EpCAM) and thymus cell antigen 1 (Thy-1)] were used for purification of freshly isolated cells. Their gene expression analysis was studied with Affymetrix Rat Expression Array 230 2.0, reverse-transcriptase polymerase chain reaction, and immunofluorescent microscopy. We found that EpCAM(+) and Thy-1(+) cells represent two different populations of cells in the oval cell niche. EpCAM(+) cells express the classical oval cell markers (alpha-fetoprotein, cytokeratin-19, OV-1 antigen, a6 integrin, and connexin 43), cell surface markers recently identified by us (CD44, CD24, EpCAM, aquaporin 5, claudin-4, secretin receptor, claudin-7, V-ros sarcoma virus oncogene homolog 1, cadherin 22, mucin-1, and CD133), and liver-enriched transcription factors (forkhead box q. forkhead box a2, onecut 1, and transcription factor 2). Oval cells do not express previously reported hematopoietic stem cell markers Thy-1, c-kit, and CD34 or the neuroepithelial marker neural cell adhesion molecule 1. However, oval cells express a number of mesenchymal markers including vimentin, mesothelin, bone morphogenetic protein 7, and Tweak receptor (tumor necrosis factor receptor superfamily, member 12A). A group of novel differentially expressed oval cell genes is also presented. It is shown that Thy-1(+) cells are mesenchymal cells with characteristics of myofibroblasts/activated stellate cells. Transplantation experiments reveal that EpCAM(+) cells are true progenitors capable of repopulating injured rat liver. Conclusion: We have shown that EpCAM(+) oval cells are bipotential adult hepatic epithelial progenitors. These cells display a mixed epithelial/mesenchymal phenotype that has not been recognized previously. They are valuable candidates for liver cell therapy.