Our laboratory focuses upon the development of liver cell-based therapies. The overall goals include obtaining insights into transplanted hepatocyte biology, such as engraftment of transplanted cells in the liver, mechanisms of gene regulation and proliferation in transplanted hepatocytes, the effect of the liver microenvironment upon engraftment, survival, proliferation and function of transplanted cells. Moreover, we are isolating and characterizing progenitor cells from the fetal human liver for applications, including development of novel models of human disease. The laboratory collaborates with a number of investigators within the Liver Center or elsewhere as necessary.
A variety of rodent models, including transgenic HBV mice, SCID mice, transgenic uPA mice, the Gunn rat, the Nagase analbuminemic rat, the dipeptidyl peptidase IV deficient (DPPIV-) rat, and the Long Evans Cinnamon rat are available for conducting experiments. Several of these animals provide unique genetic models for studying hepatic pathophysiology. In addition, animal models where acute or chronic liver injury is induced with various hepatotoxins, including cell cycle regulators are utilized. The DPPIV- rat-based transplantation systems have been particularly helpful for analyzing the fate of transplanted adult and fetal hepatocytes, as well as progenitor liver cells. Efforts are currently ongoing to mutate the DPPIV gene in the mouse by homologous recombination in embryonic stem cells. Various studies include analysis of mechanisms by which transplanted cells integrate in the liver parenchyma, to establish mechanisms that regulate entry of transplanted hepatocytes into the liver lobule, and to demonstrate how the mass of transplanted hepatocytes can be increased in the liver. Studies are conducted to examine whether liver repopulation with hepatocyte transplantation could correct metabolic function in chronic liver disease and improve survival in animals with acute liver failure. Related studies are aimed at culturing progenitor cells from the fetal human liver and analyzing mechanisms of cell differentiation, including after transplantation in immunodeficient animals. The studies utilize microarray-based gene expression analysis, as well as established cell and molecular biology methods. Other studies concern development of mechanisms by which hepatocytes could be made resistant to infection with hepatitis viruses. Further studies concern mechanisms of gene transfer in hepatocytes with retroviral or adenoviral vectors. A number of studies are ongoing concerning liver growth control mechanisms in the context of cell ploidy and its regulation by pro-oxidant mechanisms. These studies are aimed at obtaining novel insights into ways to repopulate the liver. Experiments are planned in primates or large animals for advancing toward clinical applications.
References
NCBI PubMed search of "S. Gupta"
Petersen J. Dandri M, Gupta S, Rogler CE. Liver repopulation with xenogenic hepatocytes in B and T cell-deficient mice leads to chronic hepadnavirus infection and clonal growth of hepatocellular carcinoma. Proc Natl Acad Sci (USA) 1998;95:310-315.
Ott M, Stockert RJ, Ma Q, Gagandeep S, Gupta S. Simultaneous upregulation of viral receptor expression and DNA synthesis is required for increasing efficiency of retroviral hepatic gene transfer. J Biol Chem 1998;273:11954-11961.
Rajvanshi P, Bhargava KK, Afriye M, Camaya M, Gagandeep S, Vasa SRG, Palestro CJ, Gupta S. Human serum albumin microspheres approximate initial organ-specific biodistributions of transplanted hepatocytes and are effective cell surrogates for safety studies. Cell Transplant 1998;7:275-283.
Das S, Ott M, Yamane A, Tsai W, Gromeier M, Lahser F, Gupta S, Dasgupta A. A small yeast RNA blocks hepatitis C virus internal ribosome entry site (HCV IRES)-mediated translation and inhibits replication of a chimeric poliovirus under translational control of the HCV IRES element. J Virol 1998;72:5638-5647.
Rajvanshi P, Liu D, Ott M, S Gagandeep, Schilsky M, Gupta S. Ploidy-based fractionation of rat hepatocytes with varying metabolic potential, proliferative capacity and retroviral gene transfer. Exp Cell Res 1998; 244:405-419.
Gupta S, Rajvanshi P, Sokhi RP, Slehria S, Yam A, Kerr A, Novikoff PM. Entry and integration of transplanted hepatocytes in liver plates occur by disruption of hepatic sinusoidal endothelium. Hepatology 1999;29:509-519.
Gupta S, Rajvanshi P, Sokhi R, Vaidya S, Irani AN, Gorla GR. Position-specific gene expression in the liver lobule is directed by the microenvironment and not by the previous cell differentiation state. J Biol Chem 1999; 274:2157-2165.
Ott M, Rajvanshi P, Sokhi R, Alpini G, Aragona E, Dabeva M, Shafritz DA, Gupta S. Differentiation-specific regulation of transgene expression in a diploid epithelial cell line derived from the normal F344 rat liver. J Pathol 1999;187:365-373.
Gupta S, Rajvanshi P, Aragona E, Yerneni PR, Lee C-D, Burk RD. Transplanted hepatocytes proliferate differently after CCl4 treatment and hepatocyte growth factor infusion. Am J Physiol 1999;276:G629-638.
Rajvanshi P, Fabrega A, Bhargava KK, Kerr A, Pollack G, Blanchard J, Palestro CJ, Gupta S. Rapid clearance of hepatocytes from pulmonary capillaries in rats allows development of surrogates for testing safety of liver repopulation. J Hepatol 1999;30:299-310.
Sigal SH, Rajvanshi P, Gorla GR, Saxena R, Sokhi RP, Gebhardt DF, Jr., Reid LM, Gupta S. Partial hepatectomy-induced polyploidy attenuates hepatocyte replication and activates cell aging events. Am J Physiol 1999;276:G1260-G1272.
Gagandeep S, Ott M, Sokhi R, Gupta S. Rapid clearance of syngeneic transplanted hepatocytes following transduction with E-1-deleted adenovirus indicates early host immune responses and offers novel ways for studying viral vector, target cell and host interactions. Gene Ther 1999;6:729-736.
Ott M, Ma Q, Li B, Gagandeep S, Rogler LE, Gupta S. Regulation of hepatitis B virus expression in progenitor and differentiated cell-types: evidence for negative transcriptional control in nonpermissive cells. Gene Expression 1999;8:175-186.
Guha C, Sharma A, Gupta S, Alfieri A, Gorla GR, Gagandeep S, Sokhi R, Roy-Chowdhury N, Tanaka KE, Vikram B, Roy-Chowdhury J. Amelioration of radiation-induced liver damage in partially hepatectomized rats by hepatocyte transplantation. Cancer Res 1999;59:5871-4.
Bhargava KK, Palestro CJ, Camaya MV, Rajvanshi P, Gupta S. Radionuclide analysis of drug-induced blood pool changes in liver and other organs. J Nucl Med 2000; 41:474-9.
Gupta S, Rajvanshi P, Irani AN, Palestro CJ, Bhargava KK. Integration and proliferation of transplanted cells in hepatic parenchyma following D-galactosamine-induced acute injury in F344 rats. J Pathol 2000;190:203-210.
Gagandeep S, Ott M, Nisen PD, DePinho RA, Gupta S. Overexpression of Mad transcription factor inhibits proliferation of cultured human hepatocellular carcinoma cells along with tumor formation in immunodeficient animals. J Gene Med 2000;2:117-127.
Gagandeep S, Sokhi R, Slehria S, Gorla GR, Furgiuele J, DePinho RA, Gupta S. Hepatocyte transplantation improves survival in mice with liver toxicity induced by hepatic overexpression of Mad1 transcription factor. Molec Ther 2000;1:358-365.
Gagandeep S, Rajvanshi P, Sokhi R, Slehria S, Palestro CJ, Bhargava KK, Gupta S. Transplanted hepatocytes engraft, survive and proliferate in the liver of rats with carbon tetrachloride-induced cirrhosis. J Pathol 2000;190: in press.
Sokhi RP, Rajvanshi P, Gupta S. Transplanted reporter cells help in defining onset of hepatocyte proliferation during the life of F344 rats. Am J Physiol Gastroint Liver Physiol 2000; in press.
Gupta S, Rajvanshi P, Malhi H, Sokhi RP, Slehria S, Vasa SRG, Dabeva M, Shafritz DA, Kerr A. Cell transplantation causes loss of gap junctions and activates GGT expression permanently in host liver. Am J Physiol Gastroint Liver Physiol 2000; in press.
Schilsky ML, Irani AN, Gorla GR, Volenberg I, Gupta S. Biliary copper excretion capacity in intact animals: correlation between ATP7B gene function, hepatic mass and copper excretion. J Biochem Mol Toxicol 2000; 13: in press.
Zahler MH, Irani A, Malhi H, Reutens AT, Albanese C, Bouzahzah B, Joyce D, Gupta S, Pestell RG. The application of a lentiviral vector for gene transfer in fetal human hepatocytes. J Gene Med 2000; in press.
Badve S, Logdberg L, Sokhi R, Sigal SH, Botros N, Chae S, Das KM, Gupta S. An antigen reacting with Das-1 monoclonal antibody is ontogenically regulated in diverse organs including liver and indicates sharing of developmental mechanisms among cell lineages. Pathobiology 2000; in press.
File Updated 04/00