Experimental Model for Successful Liver Cell Therapy by Lenti TTR-YapERT2 Transduced Hepatocytes with Tamoxifen Control of Yap Subcellular Location

• Published in: Scientific reports 2016-01, Vol.6 (1), p.19275-19275, Article 19275
• Main Authors: Yovchev, Mladen, Jaber, Fadi L., Lu, Zhonglei, Patel, Shachi, Locker, Joseph, Rogler, Leslie E., Murray, John W., Sudol, Marius, Dabeva, Mariana D., Zhu, Liang, Shafritz, David A.
• Format: Article
• Language: English
• Subjects: 631/61; 631/61/490; Animals; Cell- and Tissue-Based Therapy; Dysplasia; Fusion protein; Gene Expression; Genes, Reporter; Genetic Vectors - genetics; Hepatocytes; Hepatocytes - drug effects; Hepatocytes - metabolism; Hepatocytes - transplantation; Humanities and Social Sciences; Lentivirus - genetics; Liver; Liver diseases; Liver Regeneration; Liver transplantation; Models, Animal; multidisciplinary; Nuclear Proteins - genetics; Parenchyma; Prealbumin - genetics; Promoter Regions, Genetic; Protein Transport; Rats; Recombinant Fusion Proteins; Repopulation; Rodents; Science; Tamoxifen; Tamoxifen - pharmacology; Transcription Factors - genetics; Transduction, Genetic; Translation; Transthyretin; Yes-associated protein
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep19275

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.