Hepatocyte transplantation has an immense potential for gene therapy and for treating acute liver failure. Because hepatocytes possess the cellular machinery to express a variety of genes, their use for ex-vivo gene therapy is particularly attractive. Similarly, hepatocyte transplantation should provide novel therapies for acute liver failure, which currently results in unacceptable mortalities of greater than 80%. Although orthotopic liver transplantation can be employed in acute liver failure, this is a formidable and irreversible procedure. In contrast, advantages of hepatocyte transplantation include its technical simplicity, the possibility of transplanting cells prepared from a single liver into multiple recipients and the potential to cryopreserve and transplant cells at a short notice. However, despite a great urgency in applying hepatocyte transplantation in humans, a better understanding of the biology of transplanted hepatocytes is required for an optimal usage. We hypothesize that the success of hepatocyte transplantation requires a) identification of permissive conditions for hepatocyte survival and function, b) identification of methods to increase the mass of transplanted hepatocytes, and c) optimization of the time and dose of cells required for therapeutic applications. To begin addressing these critical issues, we developed novel systems with genetically marked hepatocytes to unequivocally distinguish between transplanted and host cells. Also, we demonstrated that transplanted hepatocytes survive and function most optimally in the liver. We now propose to examine mechanisms regulating proliferation and fate of transplanted hepatocytes in liver. We will examine the proliferative capacity of transplanted hepatocytes and determine whether use of liver regenerative stimuli could augment the mass of transplanted hepatocytes. As transplantation of hepatocytes into the liver may be limited by the capacity of the hepatic vascular bed, we will determine the safety of hepatocyte transplantation. Using insights derived from these studies, we will develop strategies for massive reconstitution of the host liver. These strategies will be tested in powerful animal models of genetic metabolic disease. Also, animal models of acute liver failure will be used to define the timing, dose and value of hepatocyte transplantation, a well as simultaneous administration of hepatic growth factors. Finally, hepatocyte precursor cells will be used to determine their value compared with primary hepatocytes. Completion of these proposed studies will greatly advance our fundamental knowledge of hepatocyte transplantation and help move this technology from the laboratory to the bedside.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK046952-04
Application #
2414851
Study Section
Metabolic Pathology Study Section (MEP)
Project Start
1994-06-20
Project End
1998-04-30
Budget Start
1997-05-01
Budget End
1998-04-30
Support Year
4
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Albert Einstein College of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
009095365
City
Bronx
State
NY
Country
United States
Zip Code
10461
Viswanathan, Preeti; Gupta, Priya; Kapoor, Sorabh et al. (2016) Thalidomide promotes transplanted cell engraftment in the rat liver by modulating inflammation and endothelial integrity. J Hepatol 65:1171-1178
Viswanathan, Preeti; Kapoor, Sorabh; Kumaran, Vinay et al. (2014) Etanercept blocks inflammatory responses orchestrated by TNF-? to promote transplanted cell engraftment and proliferation in rat liver. Hepatology 60:1378-88
Enami, Yuta; Joseph, Brigid; Bandi, Sriram et al. (2012) Molecular perturbations restrict potential for liver repopulation of hepatocytes isolated from non-heart-beating donor rats. Hepatology 55:1182-92
Kumar, Mukesh; Bandi, Sriram; Cheng, Kang et al. (2011) Transplantation of human cells in the peritoneal cavity of immunodeficient mice for rapid assays of hepatitis B virus replication. Xenotransplantation 18:380-9
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Joseph, Brigid; Kapoor, Sorabh; Schilsky, Michael L et al. (2009) Bile salt-induced pro-oxidant liver damage promotes transplanted cell proliferation for correcting Wilson disease in the Long-Evans Cinnamon rat model. Hepatology 49:1616-24
Bhargava, Kuldeep K; Joseph, Brigid; Ananthanarayanan, Meenakshisundaram et al. (2009) Adenosine triphosphate-binding cassette subfamily C member 2 is the major transporter of the hepatobiliary imaging agent (99m)Tc-mebrofenin. J Nucl Med 50:1140-6
Cheng, Kang; Benten, Daniel; Bhargava, Kuldeep et al. (2009) Hepatic targeting and biodistribution of human fetal liver stem/progenitor cells and adult hepatocytes in mice. Hepatology 50:1194-203

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