Our general hypothesis is that transplanted liver cells will survive and function in the context of a permissive microenvironment, best exemplified by the liver. A variety of interactions between microenvironmental factors, other types of liver cells, and soluble factors could regulate engraftment of transplanted cells in the liver. Also, cell therapy requires creation of an adequate mass of transplanted cells in the liver. To demonstrate whether transplanted cells can engraft and proliferate in specific disorders, studies in suitable animal models are necessary. Such studies need to include analysis of human cells as well as assays of stem/progenitor cells for establishing appropriate clinical strategies. Progress in our laboratory over the past several years has led to the development of working models of transplanted cell engraftment and proliferation in the liver. Several important mechanisms have been identified that regulate the entry of transplanted cells in the liver parenchyma and further determine whether transplanted cells will proliferate or not. Specific perturbations in the host liver that promote cell engraftment include analysis of cells in liver sinusoids, modulations in the liver microenvironment and aspects of the biological properties of transplanted cells themselves. Genotoxic injury in native hepatocytes that spare transplanted cells from injury appears to be highly effective in promoting transplanted cell proliferation. A major goal of our continuing studies in this area concerns development of novel mechanisms in liver repopulation. We propose a series of studies to further define cell engraftment in the normal and the diseased liver of animals. We will study the fate of human liver cells in immunodeficient mice to generate further animal models. We will determine whether transplanted cells will proliferate following novel ways to induce genotoxic injury in the liver of recipient animals prior to cell transplantation. We will use these principles to approach correction of metabolic and genetic disorders in animals by liver-directed cell therapy. Completion of our studies will provide new knowledge in the areas of liver repopulation, stem cell biology and cell therapy. Our studies will provide valuable preclinical information for eventual applications of cell therapy in people.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Metabolic Pathology Study Section (MEP)
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Doo, Edward
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Albert Einstein College of Medicine
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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
Cheng, Kang; Follenzi, Antonia; Surana, Manju et al. (2010) Switching of mesodermal and endodermal properties in hTERT-modified and expanded fetal human pancreatic progenitor cells. Stem Cell Res Ther 1:6
Krohn, Natan; Kapoor, Sorabh; Enami, Yuta et al. (2009) Hepatocyte transplantation-induced liver inflammation is driven by cytokines-chemokines associated with neutrophils and Kupffer cells. Gastroenterology 136:1806-17
Cheng, Kang; Gupta, Sanjeev (2009) Quantitative tools for assessing the fate of xenotransplanted human stem/progenitor cells in chimeric mice. Xenotransplantation 16:145-51
Joseph, Brigid; Bhargava, Kuldeep K; Tronco, Gene G et al. (2009) Molecular pathway-specific 99mTc-N-(3-bromo-2,4,6-trimethyacetanilide) iminodiacetic acid liver imaging to assess innate immune responses induced by cell transplantation. Nucl Med Commun 30:126-33
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

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