{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T03:48:13Z","timestamp":1778644093169,"version":"3.51.4"},"reference-count":33,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","license":[{"start":{"date-parts":[[2018,11,20]],"date-time":"2018-11-20T00:00:00Z","timestamp":1542672000000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Hepatol Commun"],"published-print":{"date-parts":[[2019,1]]},"abstract":"<jats:p>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<jats:sup>\u2212<\/jats:sup> (dipeptidyl peptidase\u20104) rats and <jats:italic toggle=\"yes\">Ugt1a1<\/jats:italic> (uridinediphosphoglucuronate glucuronosyltransferase 1a1)\u2010deficient Gunn rats (model of Crigler\u2010Najjar syndrome type 1), both models without underlying liver injury, for up to 1 year by transplanting lenti\u2010hYAP\u2010ERT2 (mutated estrogen receptor ligand\u2010binding domain 2)\u2010transduced hepatocytes (YAP\u2010Hc). Yap (yes\u2010associated protein) nuclear translocation\/function in YAP\u2010Hc was regulated by tamoxifen. Repopulating YAP\u2010Hc and host hepatocytes were fluorescence\u2010activated cell sorting\u2013purified and their transcriptomic profiles compared by RNAseq. After 1 year of liver repopulation, YAP\u2010Hc clusters exhibited normal morphology, integration into hepatic plates and hepatocyte\u2010specific gene expression, without dysplasia, dedifferentiation, or tumorigenesis. RNAseq analysis showed up\u2010regulation 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\u2010Hc. In Gunn rats transplanted with YAP\u2010Hc+tamoxifen, there was a 65%\u201081% decline in serum bilirubin over 6 months versus 8%\u201020% with control\u2010Hc, representing a 3\u20104\u2010fold increase in therapeutic response. This correlated with liver repopulation as demonstrated by the presence of <jats:italic toggle=\"yes\">Ugt1a1<\/jats:italic>\u2010positive hepatocyte clusters in livers and western blot analysis of tissue homogenates. <jats:italic toggle=\"yes\">Conclusion:<\/jats:italic> Tamoxifen\u2010regulated nuclear translocation\/function of hYAP\u2010ERT2 enabled long\u2010term repopulation of DPPIV<jats:sup>\u2212\/\u2212<\/jats:sup> and Gunn rat livers by hYAP\u2010ERT2\u2010transduced 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.<\/jats:p>","DOI":"10.1002\/hep4.1278","type":"journal-article","created":{"date-parts":[[2018,11,20]],"date-time":"2018-11-20T13:46:10Z","timestamp":1542721570000},"page":"129-146","source":"Crossref","is-referenced-by-count":8,"title":["Genes and Pathways Promoting Long\u2010Term Liver Repopulation by\u00a0Ex Vivo\u00a0hYAP\u2010ERT2 Transduced Hepatocytes and Treatment of Jaundice in Gunn Rats"],"prefix":"10.1097","volume":"3","author":[{"given":"Esther A.","family":"Peterson","sequence":"first","affiliation":[{"name":"Department of Medicine,Marion Bessin Liver Research Center, Albert Einstein College of Medicine,Bronx,NY"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zsuzsanna","family":"Polgar","sequence":"additional","affiliation":[{"name":"Department of Medicine,Marion Bessin Liver Research Center, Albert Einstein College of Medicine,Bronx,NY"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gnanapackiam S.","family":"Devakanmalai","sequence":"additional","affiliation":[{"name":"Department of Medicine,Marion Bessin Liver Research Center, Albert Einstein College of Medicine,Bronx,NY"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yanfeng","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Medicine,Marion Bessin Liver Research Center, Albert Einstein College of Medicine,Bronx,NY"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fadi L.","family":"Jaber","sequence":"additional","affiliation":[{"name":"Department of Medicine,Marion Bessin Liver Research Center, Albert Einstein College of Medicine,Bronx,NY"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wei","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology,Marion Bessin Liver Research Center, Albert Einstein College of Medicine,Bronx,NY"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xia","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Medicine,Marion Bessin Liver Research Center, Albert Einstein College of Medicine,Bronx,NY"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Niloy J.","family":"Iqbal","sequence":"additional","affiliation":[{"name":"Department of Developmental and Molecular Biology,Marion Bessin Liver Research Center, Albert Einstein College of Medicine,Bronx,NY"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John W.","family":"Murray","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Structural Biology,Marion Bessin Liver Research Center, Albert Einstein College of Medicine,Bronx,NY"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Namita","family":"Roy\u2010Chowdhury","sequence":"additional","affiliation":[{"name":"Department of Medicine,Marion Bessin Liver Research Center, Albert Einstein College of Medicine,Bronx,NY"},{"name":"Department of Genetics,Albert Einstein College of Medicine,Bronx,NY"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wilber","family":"Quispe\u2010Tintaya","sequence":"additional","affiliation":[{"name":"Department of Genetics,Albert Einstein College of Medicine,Bronx,NY"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexander Y.","family":"Maslov","sequence":"additional","affiliation":[{"name":"Department of Genetics,Albert Einstein College of Medicine,Bronx,NY"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tatyana L.","family":"Tchaikovskaya","sequence":"additional","affiliation":[{"name":"Department of Medicine,Marion Bessin Liver Research Center, Albert Einstein College of Medicine,Bronx,NY"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yogeshwar","family":"Sharma","sequence":"additional","affiliation":[{"name":"Department of Medicine,Marion Bessin Liver Research Center, Albert Einstein College of Medicine,Bronx,NY"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leslie E.","family":"Rogler","sequence":"additional","affiliation":[{"name":"Department of Medicine,Marion Bessin Liver Research Center, Albert Einstein College of Medicine,Bronx,NY"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sanjeev","family":"Gupta","sequence":"additional","affiliation":[{"name":"Department of Medicine,Marion Bessin Liver Research Center, Albert Einstein College of Medicine,Bronx,NY"},{"name":"Department of Pathology,Albert Einstein College of Medicine,Bronx,NY"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liang","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Medicine,Marion Bessin Liver Research Center, Albert Einstein College of Medicine,Bronx,NY"},{"name":"Department of Developmental and Molecular Biology,Marion Bessin Liver Research Center, Albert Einstein 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