斑马鱼
祖细胞
mTORC1型
细胞生物学
转分化
肝再生
再生(生物学)
PI3K/AKT/mTOR通路
肝损伤
肝细胞
细胞生长
干细胞
生物
信号转导
内分泌学
生物化学
体外
基因
作者
Jianbo He,Jingying Chen,Xiangyong Wei,Hui Leng,Hongliang Mu,Peng Cai,Lingfei Luo
出处
期刊:Hepatology
[Wiley]
日期:2019-08-12
卷期号:70 (6): 2092-2106
被引量:50
摘要
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.
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