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Hepatocyte transplantation is an attractive alternative to liver transplantation. Thus far, however, extensive liver repopulation by adult hepatocytes has required ongoing genetic, physical, or chemical injury to host liver. We hypothesized that providing a regulated proliferative and/or survival advantage to transplanted hepatocytes should enable repopulation in a normal liver microenvironment. Here, we repopulated livers of DPPIV −  (dipeptidyl peptidase‐4) rats and  Ugt1a1  (uridinediphosphoglucuronate glucuronosyltransferase 1a1)‐deficient Gunn rats (model of Crigler‐Najjar syndrome type 1), both models without underlying liver injury, for up to 1 year by transplanting lenti‐hYAP‐ERT2 (mutated estrogen receptor ligand‐binding domain 2)‐transduced hepatocytes (YAP‐Hc). Yap (yes‐associated protein) nuclear translocation/function in YAP‐Hc was regulated by tamoxifen. Repopulating YAP‐Hc and host hepatocytes were fluorescence‐activated cell sorting–purified and their transcriptomic profiles compared by RNAseq. After 1 year of liver repopulation, YAP‐Hc clusters exhibited normal morphology, integration into hepatic plates and hepatocyte‐specific gene expression, without dysplasia, dedifferentiation, or tumorigenesis. RNAseq analysis showed up‐regulation of 145 genes promoting cell proliferation and 305 genes suppressing apoptosis, including hepatocyte growth factor and connective tissue growth factor among the top 30 in each category and provided insight into the mechanism of cell competition that enabled replacement of host hepatocytes by YAP‐Hc. In Gunn rats transplanted with YAP‐Hc+tamoxifen, there was a 65%‐81% decline in serum bilirubin over 6 months versus 8%‐20% with control‐Hc, representing a 3‐4‐fold increase in therapeutic response. This correlated with liver repopulation as demonstrated by the presence of  Ugt1a1 ‐positive hepatocyte clusters in livers and western blot analysis of tissue homogenates.  Conclusion:  Tamoxifen‐regulated nuclear translocation/function of hYAP‐ERT2 enabled long‐term repopulation of DPPIV −/−  and Gunn rat livers by hYAP‐ERT2‐transduced hepatocytes without tumorigenesis. This cell transplantation strategy may offer a potential therapy for most of the inherited monogenic liver diseases that do not exhibit liver injury.

Genes and Pathways Promoting Long‐Term Liver Repopulation by Ex Vivo hYAP‐ERT2 Transduced Hepatocytes and Treatment of Jaundice in Gunn Rats