Mammalian Target of Rapamycin Complex 1 Signaling Is Required for the Dedifferentiation From Biliary Cell to Bipotential Progenitor Cell in Zebrafish Liver Regeneration

Abstract

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.

Cell Plasticity in Liver Regeneration

“…In addition, mTORC1 and the BMP pathway were found to regulate the conversion of biliary epithelial cells to hepatocytes in zebrafish [55,56]. Inhibition of the mTORC1 signaling pathway abolished the conversion from biliary epithelial cells to hepatoblast-like cells via decreased Urb2-mediated protein synthesis [56], whereas the BMP pathway controlled the conversion of biliary epithelial cells through Tbx2b expression [55]. These studies together show several important signaling and epigenetic factors underlying biliary epithelial cell plasticity in zebrafish.…”

“…Inhibition of the bromodomain and extraterminal (BET) protein blocked the dedifferentiation of biliary epithelial cells to hepatoblastlike cells via reduced Prox1 and Hnf4a induction [54]. In addition, mTORC1 and the BMP pathway were found to regulate the conversion of biliary epithelial cells to hepatocytes in zebrafish [55,56]. Inhibition of the mTORC1 signaling pathway abolished the conversion from biliary epithelial cells to hepatoblast-like cells via decreased Urb2-mediated protein synthesis [56], whereas the BMP pathway controlled the conversion of biliary epithelial cells through Tbx2b expression [55].…”

Liver progenitor cell-driven liver regeneration

“…Using this model, we recently reported that BMP signaling regulates LPC-driven liver regeneration through Tbx2a and Id2a 75 and that bromodomain and extraterminal proteins (BET), Hdac1, Kdm1a, Sox9b, and Notch3 regulate LPC-driven liver regeneration 76,113,114 . Using the same zebrafish model, two other groups also reported that mTORC1 signaling regulates LPC-driven liver regeneration 115,116 .…”

Roles of mTOR Signaling in Tissue Regeneration

“…After extreme liver damage, regeneration is achieved via cholangiocytes transdifferentiation rather than self-replication, in zebrafish [174,175] and mice [176,177] (Figure 3E). The mTOR signaling pathway mediates liver regeneration after PH and initiates the transdifferentiation of biliary epithelial cells (BECs) after extreme liver injury [178,179].…”

“…Contributions of non-parenchymal cells (NPCs) can also be important for liver regeneration [174,176,177,179,200]. Expansion of BECs during ductular reaction (DR) is promoted by mTORC1 signaling after extreme liver injury in zebrafish and mice [179,200] (Figure 3E).…”