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

Scientific Reports
Mladen YovchevD A Shafritz

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.

References

Feb 15, 1991·Proceedings of the National Academy of Sciences of the United States of America·K P PonderS L Woo
Apr 4, 1997·Science·G K Michalopoulos, M C DeFrances
Aug 28, 1997·Biochemical and Biophysical Research Communications·R FeilP Chambon
May 15, 1998·The New England Journal of Medicine·I J FoxS C Strom
Aug 30, 2001·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·B AkhurstG C Yeoh
Oct 5, 2001·The American Journal of Pathology·J S SandhuD A Shafritz
Aug 6, 2002·Molecular Therapy : the Journal of the American Society of Gene Therapy·Tuan Huy NguyenDidier Trono
Aug 7, 2003·Proceedings of the National Academy of Sciences of the United States of America·Xin WangMarkus Grompe
Jan 15, 2004·Seminars in Liver Disease·Tania A RoskamsValeer J Desmet
Feb 24, 2005·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·George K MichalopoulosWilliam C Bowen
Mar 26, 2005·Cell Transplantation·Rafal P WitekBryon E Petersen
May 11, 2005·Cell Transplantation·Giovanni AmbrosinoLorenzo D'Antiga
May 18, 2007·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Dirk NierhoffDavid A Shafritz
Nov 6, 2007·Current Biology : CB·Fernando D CamargoThijn R Brummelkamp
Sep 22, 2009·Journal of Internal Medicine·E FitzpatrickA Dhawan
Jan 19, 2010·The International Journal of Biochemistry & Cell Biology·David A Shafritz, Michael Oertel
Jan 19, 2010·Proceedings of the National Academy of Sciences of the United States of America·Hai SongYingzi Yang
Jan 19, 2010·Proceedings of the National Academy of Sciences of the United States of America·Li LuRandy L Johnson
Apr 21, 2010·Proceedings of the National Academy of Sciences of the United States of America·Kwang-Pyo LeeDae-Sik Lim
May 5, 2010·Genes & Development·Bin ZhaoKun-Liang Guan
Oct 19, 2010·Developmental Cell·Duojia Pan
Mar 13, 2012·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·George K Michalopoulos
Aug 28, 2012·Gastroenterology·Regina Español-SuñerIsabelle A Leclercq
Nov 20, 2012·Oncogene·M Sudol
Apr 13, 2013·Journal of Hepatology·Stefano FagiuoliGiuseppe Remuzzi
Oct 12, 2013·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Tohru Itoh, Atsushi Miyajima
Apr 5, 2014·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Branden D TarlowMarkus Grompe
Jun 7, 2014·Cell·Dean YimlamaiFernando D Camargo

❮ Previous
Next ❯

Methods Mentioned

BETA
transgenic
PCR

Software Mentioned

Zeiss Axiovision
ImageJ
Primer3

Related Concepts

Related Feeds

Allogenic & Autologous Therapies

Allogenic therapies are generated in large batches from unrelated donor tissues such as bone marrow. In contrast, autologous therapies are manufactures as a single lot from the patient being treated. Here is the latest research on allogenic and autologous therapies.

CREs: Gene & Cell Therapy

Gene and cell therapy advances have shown promising outcomes for several diseases. The role of cis-regulatory elements (CREs) is crucial in the design of gene therapy vectors. Here is the latest research on CREs in gene and cell therapy.