De novo formation of the biliary system by TGFβ-mediated hepatocyte transdifferentiation.

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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, i.e., in the presence of a fully developed scaffold and niche1. Here we show that transdifferentiation of hepatocytes in the liver can build a structure that failed to form in development—the biliary system in mice that mimic 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, i.e., incomplete and transient biliary differentiation as an adaptation to cell injury, based on previous studies in mice with a fully developed biliary system3–6. We show that, in contrast to bile duct development7–9, de novo bile duct formation by hepatocyte transdifferentiation is independent of NOTCH signaling. We identify TGFβ signaling as the driver of this compensatory mechanism and show that it is active in some patients with ALGS. We also show that TGFβ signaling can be targeted to enhance the formation of the biliary system from hepatocytes, and that the transdifferentiation-inducing signals and remodeling 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 therapy of ALGS and other cholestatic liver diseases.