Mammalian Target of Rapamycin Complex 1 Signaling Is Required for the Dedifferentiation From Biliary Cell to Bipotential Progenitor Cell in Zebrafish Liver Regeneration
Mammalian Target of Rapamycin Complex 1 Signaling Is Required for the Dedifferentiation From Biliary Cell to Bipotential Progenitor Cell in Zebrafish Liver Regeneration
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斑马鱼肝脏再生中从胆细胞到双能祖细胞的去分化需要雷帕霉素复合物 1 信号传导的哺乳动物靶标
DOI：
10.1002/hep.30790
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发表时间：
2019-08-12
期刊：
影响因子：
13.5
通讯作者：
Luo, Lingfei
中科院分区：
文献类型：
--
作者：
He, Jianbo;Chen, Jingying;Luo, Lingfei
肝脏具有很高的再生能力。在三分之二部分肝切除术后，肝细胞增殖并有助于肝再生。严重肝损伤后，残余肝细胞增殖受阻，胆管上皮细胞（biliary epithelial cells，BECs）失去形态，表达肝母细胞和内胚层标志，去分化为双能祖细胞（bipotential progenitor cells，BP-PCs），然后增殖并再分化为成熟肝细胞。关于极端肝损伤后BP-PC形成的机制知之甚少。使用斑马鱼肝脏极端损伤模型，我们发现哺乳动物雷帕霉素复合物靶蛋白1（mTORC 1）信号调节BEC的去分化和BP-PC的增殖。mTORC 1信号在极端肝细胞消融期间在BEC中上调，并在后期肝再生中持续表达。在肝细胞消融之前通过早期化学处理抑制mTORC 1阻断了BEC向BP-PC的去分化。肝损伤后晚期mTORC 1抑制降低了BP-PC衍生的肝细胞和BEC的增殖，但不影响BP-PC再分化。mTOR和raptor突变体在BEC转分化中表现出缺陷，包括去分化、BP-PC增殖和再分化，类似于化学抑制。结论：mTORC 1信号通过调节BEC的去分化以及BP-PC衍生的肝细胞和BEC的增殖来控制BEC驱动的肝再生。
The liver has a high regenerative capacity. Upon two-thirds partial hepatectomy, the hepatocytes proliferate and contribute to liver regeneration. After severe liver injury, when the proliferation of residual hepatocytes is blocked, the biliary epithelial cells (BECs) lose their morphology and express hepatoblast and endoderm markers, dedifferentiate into bipotential progenitor cells (BP-PCs), then proliferate and redifferentiate into mature hepatocytes. Little is known about the mechanisms involved in the formation of BP-PCs after extreme liver injury. Using a zebrafish liver extreme injury model, we found that mammalian target of rapamycin complex 1 (mTORC1) signaling regulated dedifferentiation of BECs and proliferation of BP-PCs. mTORC1 signaling was up-regulated in BECs during extreme hepatocyte ablation and continuously expressed in later liver regeneration. Inhibition of mTORC1 by early chemical treatment before hepatocyte ablation blocked the dedifferentiation from BECs into BP-PCs. Late mTORC1 inhibition after liver injury reduced the proliferation of BP-PC-derived hepatocytes and BECs but did not affect BP-PC redifferentiation. mTOR and raptor mutants exhibited defects in BEC transdifferentiation including dedifferentiation, BP-PC proliferation, and redifferentiation, similar to the chemical inhibition. Conclusion: mTORC1 signaling governs BEC-driven liver regeneration by regulating the dedifferentiation of BECs and the proliferation of BP-PC-derived hepatocytes and BECs.