Human ESC/iPSC-Derived Hepatocyte-like Cells Achieve Zone-Specific Hepatic Properties by Modulation of WNT Signaling.
Human ESC/iPSC-Derived Hepatocyte-like Cells Achieve Zone-Specific Hepatic Properties by Modulation of WNT Signaling.
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DOI：
10.1016/j.ymthe.2017.04.006
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发表时间：
2017-06
期刊：
影响因子：
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通讯作者：
Seiji Mitani;Kazuo Takayama;Yasuhito Nagamoto;K. Imagawa;F. Sakurai;M. Tachibana;R. Sumazaki;H. Mizuguchi
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文献类型：
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作者：
Seiji Mitani;Kazuo Takayama;Yasuhito Nagamoto;K. Imagawa;F. Sakurai;M. Tachibana;R. Sumazaki;H. Mizuguchi
肝细胞的功能很大程度上取决于它们在肝小叶中的位置。尽管在过去的十年中，从人类多能干细胞中分化肝细胞的方法已经有了很大的改进，但仍然没有技术来产生具有区域特异性肝脏特性的肝细胞样细胞（hlc）。在这项研究中，我们寻找促进hlc获得区域特异性的因素。在这里，我们发现肝细胞和胆管细胞分泌的WNT7B和WNT8B在实现静脉周围区特异性特征方面发挥重要作用，如增强谷氨酰胺分泌、柠檬酸循环、细胞色素P450 (CYP) 1A2代谢和CYP1A2诱导能力。我们还发现，胆管细胞分泌的WNT抑制因子（WIF-1）对于实现门静脉周围区特异性特征（如增强尿素分泌和糖异生能力）是必要的。因此，肝细胞或胆管细胞分泌的WNT信号调节剂赋予了肝细胞区域特异性的肝脏特性。
The function of hepatocytes largely depends on their position in the liver lobule. Although the method of differentiating hepatocytes from human pluripotent stem cells has been largely improved over the past decade, there remains no technique for generating hepatocyte-like cells (HLCs) with zone-specific hepatic properties. In this study, we searched for the factors that promote acquisition of zone-specific properties of HLCs. Here, we identified that WNT7B and WNT8B secreted from hepatocytes and cholangiocytes play important roles in achieving perivenous zone-specific characteristics, such as the enhancement of glutamine secretion, citric acid cycle, cytochrome P450 (CYP) 1A2 metabolism, and CYP1A2 induction capacities. We also found that WNT inhibitory factor (WIF-1) secreted from cholangiocytes was necessary for achieving periportal zone-specific characteristics, such as the enhancement of urea secretion and gluconeogenesis capacities. Therefore, WNT signal modulators secreted from hepatocytes or cholangiocytes conferred zone-specific hepatic properties onto HLCs.