クーリャル　シモン   KURIAL　SIMONE    所属   川崎医科大学  医学部 基礎医学　解剖学    職種   特任講師
論文種別	原著
言語種別	英語
査読の有無	査読あり
表題	De novo formation of the biliary system by TGFβ-mediated hepatocyte transdifferentiation.
掲載誌名	正式名：Nature 略　 称：Nature ISSNコード：14764687/00280836
掲載区分	国外
巻・号・頁	557(7704),pp.247-251
著者・共著者	Johanna R Schaub, Kari A Huppert, Simone N T Kurial, Bernadette Y Hsu, Ashley E Cast, Bryan Donnelly, Rebekah A Karns, Feng Chen, Milad Rezvani, Hubert Y Luu, Aras N Mattis, Anne-Laure Rougemont, Philip Rosenthal, Stacey S Huppert, Holger Willenbring
発行年月	2018/05
概要	Transdifferentiation is a complete and stable change in cell identity that serves as an alternative to stem-cell-mediated organ regeneration. In adult mammals, findings of transdifferentiation have been limited to the replenishment of cells lost from preexisting structures, in the presence of a fully developed scaffold and niche1. Here we show that transdifferentiation of hepatocytes in the mouse liver can build a structure that failed to form in development-the biliary system in a mouse model that mimics the hepatic phenotype of human Alagille syndrome (ALGS)2. In these mice, hepatocytes convert into mature cholangiocytes and form bile ducts that are effective in draining bile and persist after the cholestatic liver injury is reversed, consistent with transdifferentiation. These findings redefine hepatocyte plasticity, which appeared to be limited to metaplasia, that is, incomplete and transient biliary differentiation as an adaptation to cell injury, based on previous studies in mice with a fully developed biliary system3-6. In contrast to bile duct development7-9, we show that de novo bile duct formation by hepatocyte transdifferentiation is independent of NOTCH signalling. We identify TGFβ signalling as the driver of this compensatory mechanism and show that it is active in some patients with ALGS. Furthermore, we show that TGFβ signalling can be targeted to enhance the formation of the biliary system from hepatocytes, and that the transdifferentiation-inducing signals and remodelling capacity of the bile-duct-deficient liver can be harnessed with transplanted hepatocytes. Our results define the regenerative potential of mammalian transdifferentiation and reveal opportunities for the treatment of ALGS and other cholestatic liver diseases.
DOI	10.1038/s41586-018-0075-5
PMID	29720662