title: Experimental Model for Successful Liver Cell Therapy by Lenti TTR-YapERT2 Transduced Hepatocytes with Tamoxifen Control of Yap Subcellular Location.
abstract: Liver repopulation by transplanted hepatocytes has not been achieved previously in a normal liver microenvironment. Here we report that adult rat hepatocytes transduced ex vivo with a lentivirus expressing a human YapERT2 fusion protein (hYapERT2) under control of the hepatocyte-specific transthyretin (TTR) promoter repopulate normal rat liver in a tamoxifen-dependent manner. Transplanted hepatocytes expand very slowly but progressively to produce 10% repopulation at 6 months, showing clusters of mature hepatocytes that are fully integrated into hepatic parenchyma, with no evidence for dedifferentiation, dysplasia or malignant transformation. Thus, we have developed the first vector designed to regulate the growth control properties of Yap that renders it capable of producing effective cell therapy. The level of liver repopulation achieved has significant translational implications, as it is 2-3x the level required to cure many monogenic disorders of liver function that have no underlying hepatic pathology and is potentially applicable to diseases of other tissues and organs.
authors.affiliation: Marion Bessin Liver Research Center, Division of Gastroenterology and Liver Diseases, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461.
authors.forename: Mladen
authors.initials: M
authors.lastname: Yovchev
authors.affiliation: Marion Bessin Liver Research Center, Division of Gastroenterology and Liver Diseases, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461.
authors.forename: Fadi L
authors.initials: FL
authors.lastname: Jaber
authors.affiliation: Marion Bessin Liver Research Center, Division of Gastroenterology and Liver Diseases, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461.|Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461.
authors.forename: Zhonglei
authors.initials: Z
authors.lastname: Lu
authors.affiliation: Marion Bessin Liver Research Center, Division of Gastroenterology and Liver Diseases, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461.
authors.forename: Shachi
authors.initials: S
authors.lastname: Patel
authors.affiliation: Department of Pathology, University of Pittsburgh, 200 Lothrop Street, Room S521, Pittsburgh, PA 15261.
authors.forename: Joseph
authors.initials: J
authors.lastname: Locker
authors.affiliation: Marion Bessin Liver Research Center, Division of Gastroenterology and Liver Diseases, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461.
authors.forename: Leslie E
authors.initials: LE
authors.lastname: Rogler
authors.affiliation: Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461.
authors.forename: John W
authors.initials: JW
authors.lastname: Murray
authors.affiliation: Department of Physiology, National University of Singapore, Laboratory of Cancer Signaling &Domainopathies, Yong Loo Li School of Medicine, Block MD9, 2 Medical Drive #04-01, Singapore 117597.
authors.forename: Marius
authors.initials: M
authors.lastname: Sudol
authors.affiliation: Marion Bessin Liver Research Center, Division of Gastroenterology and Liver Diseases, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461.
authors.forename: Mariana D
authors.initials: MD
authors.lastname: Dabeva
authors.affiliation: Marion Bessin Liver Research Center, Division of Gastroenterology and Liver Diseases, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461.|Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461.
authors.forename: Liang
authors.initials: L
authors.lastname: Zhu
authors.affiliation: Marion Bessin Liver Research Center, Division of Gastroenterology and Liver Diseases, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461.
authors.forename: David A
authors.initials: DA
authors.lastname: Shafritz
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins; D064987:Cell- and Tissue-Based Therapy; D015870:Gene Expression; D017930:Genes, Reporter; D005822:Genetic Vectors / Q000235:genetics; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism* / Q000637:transplantation; D016086:Lentivirus / Q000235:genetics; D008115:Liver Regeneration; D023421:Models, Animal; D009687:Nuclear Proteins / Q000235:genetics*; D011228:Prealbumin / Q000235:genetics*; D011401:Promoter Regions, Genetic; D021381:Protein Transport; D051381:Rats; D011993:Recombinant Fusion Proteins; D013629:Tamoxifen / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics*; D014161:Transduction, Genetic
chemical_list: D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D011228:Prealbumin; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; C456659:YY1AP1 protein, human; D013629:Tamoxifen