A role of Wnt/beta-catenin signals in hepatic fate specification of human umbilical cord blood-derived mesenchymal stem cells.
A role of Wnt/beta-catenin signals in hepatic fate specification of human umbilical cord blood-derived mesenchymal stem cells.
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发表时间：
2007
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通讯作者：
Y. Yoshida;T. Shimomura;Tomohiko Sakabe;K. Ishii;K. Gonda;Saori Matsuoka;Yumi Watanabe;Kazuko Takubo;H. Tsuchiya;Y. Hoshikawa;A. Kurimasa;I. Hisatome;T. Uyama;M. Terai;A. Umezawa;G. Shiota
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作者：
Y. Yoshida;T. Shimomura;Tomohiko Sakabe;K. Ishii;K. Gonda;Saori Matsuoka;Yumi Watanabe;Kazuko Takubo;H. Tsuchiya;Y. Hoshikawa;A. Kurimasa;I. Hisatome;T. Uyama;M. Terai;A. Umezawa;G. Shiota
人脐血间充质干细胞(UCBMSCs)有望成为良好的移植细胞来源。此外，人脐血间充质干细胞具有干细胞可塑性，可转分化为肝细胞。然而，所涉及的机制仍有待澄清。为了确定决定人UCBMSCs肝脏命运的重要基因和/或信号，我们分析了人端粒酶逆转录酶在UCBMSCs肝脏分化过程中的基因表达谱，UCBMSCs因感染携带端粒酶逆转录酶的逆转录病毒而永生化，但其分化潜力保持不变。5-氮杂胞苷(5-aza)/肝细胞生长因子(HGF)/抑癌素M(OSM)/成纤维细胞生长因子2(FGF2)在功能和蛋白表达方面均能有效诱导分化：白蛋白增加2.5倍，CCAAT增强子结合蛋白α增加4倍，细胞色素P450 1A1/2增加1.5倍，高碘酸-希夫染色增加8倍。因此，我们发现Wnt/β-catenin相关基因的表达下调，尽管仍有一些β-catenin位于细胞核内，但仍可观察到β-catenin沿细胞膜和细胞质的移位。通过TCF4启动子-荧光素酶分析，Fz8-小干扰RNA处理下调了细胞中的Wnt/β-catenin信号，导致了与5-azacytidine/HGF/OSM/FGF2相似的肝脏分化。此外，β-连环蛋白的亚细胞分布与5-氮杂胞苷/HGF/OSM/FGF2处理的细胞相似。总之，Wnt/β-catenin信号的抑制诱导了UCBMSCs的肝脏分化，提示Wnt/β-catenin信号在人UCBMSCs的肝脏命运调控中起着重要的作用。
Human umbilical cord blood-derived mesenchymal stem cells (UCBMSCs) are expected to be an excellent source of cells for transplantation. In addition, the stem cell plasticity of human UCBMSCs, which can transdifferentiate into hepatocytes, has been reported. However, the mechanisms involved remain to be clarified. To identify the genes and/or signals that are important in specifying the hepatic fate of human UCBMSCs, we analyzed gene expression profiles during the hepatic differentiation of UCBMSCs with human telomerase reverse transcriptase, UCBMSCs immortalized by infection with a retrovirus carrying telomerase reverse transcriptase, but whose differentiation potential remains unchanged. Efficient differentiation was induced by 5-azacytidine (5-aza)/hepatocyte growth factor (HGF)/oncostatin M (OSM)/fibroblast growth factor 2 (FGF2) treatment in terms of function as well as protein expression: 2.5-fold increase in albumin, 4-fold increase in CCAAT enhancer-binding protein alpha, 1.5-fold increase in cytochrome p450 1A1/2, and 8-fold increase in periodic acid-Schiff staining. Consequently, we found that the expression of Wnt/beta-catenin-related genes downregulated, and the translocation of beta-catenin was observed along the cell membrane and in the cytoplasm, although some beta-catenin was still in the nucleus. Downregulation of Wnt/beta-catenin signals in the cells by Fz8-small interference RNA treatment, which was analyzed with a Tcf4 promoter-luciferase assay, resulted in similar hepatic differentiation to that observed with 5-azacytidine/HGF/OSM/FGF2. In addition, the subcellular distribution of beta-catenin was similar to that of cells treated with 5-azacytidine/HGF/OSM/FGF2. In conclusion, the suppression of Wnt/beta-catenin signaling induced the hepatic differentiation of UCBMSCs, suggesting that Wnt/beta-catenin signals play an important role in the hepatic fate specification of human UCBMSCs.