Ductular metaplasia of hepatocytes : its demonstration in vivo and the study of the mechanism

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To demonstrate transdifferentiation of hepatocytes to bile dutular cells in vivo, we established a hepatocyte-lineage tracing system, in which hepatocytes from Alb^<Cre/WT>ROSA26R (β-galactosidase-positive) were transplanted into the livers of C56BL/6J mice. In chronic liver injury induced by CCl_4 or DDC in these mice, we often found β-galactosidase-positive and cytokeratin 19-positive ductules, demonstrating that ductular transdifferentiation actually occurs in vivo. In addition, we found that hepatocyes from MKK7 KO mice (MKK7^<fl/fl>Alb^<Cre/WT>) showed less prominent branching morphogenesis as compared with those from control mice (MKK7^<fl/+>Alb^<Cre/WT>).