Our laboratory focuses on development of liver cell-based therapies and relevant aspects of stem cell biology. Major efforts are directed toward understanding mechanisms by which transplanted cells may engraft, proliferate and function in the liver, obtaining insights into cell-cell interactions that may benefit transplanted cells, and addressing the potential of liver cell types for treating major diseases of interest. We work with adult or stem/progenitor cells that have been isolated from tissues and use such cells for studying mechanisms in gene regulation and/or cell differentiation, expression of therapeutic constructs, and transplantation of such cells. In other projects, we determine whether endogenous stem/progenitor cells could be activated by cell therapy approaches, including specific paracrine factors released from transplanted cells. This offers opportunities for candidate drug development aimed at modulation of relevant receptors with cytoprotective potential. The diseases of out therapeutic interest include acute liver failure (mechanisms for inducing iver regeneration), genetic deficiency states (e.g., Wilson's disease with copper toxicosis with opportunities for cell/gene therapy approaches using hepatocytes for liver repopulation), and hemophilia A (opportuniteis to address disease correction with liver sinusoidal endothelial cells, whcih are the major producers of FVIII in the body).
A variety of rodent models are used, including the hemophilia A mouse, the Gunn rat, the Nagase analbuminemic rat, the dipeptidyl peptidase IV deficient (DPPIV-) rat and the DPPIV- mouse, and the Long-Evans Cinnamon rat, etc. Animal models, where acute or chronic liver injury is induced are also available. The DPPIV- rat and mouse-based transplantation systems have been helpful for analyzing the fate of transplanted adult, fetal or stem/progenitor cells. Related studies concern cell culture analysis of stem/progenitor cells for mechanisms in cell differentiation and function. Other studies are devoted to signifiant issues in cell transplantation, e.g., cryopreservation of cells, expansion of organ donor pools through study of nonheart beating donors, as well as defining how inflammation may be controlled. Clinically used drugs are studied for translational proximity of various mechanisms. Molecular studies utilize microarray-based or deep sequencing approaches for gene expression or other established cell and molecular biology methods.
We collaborate with leading investigators at Einstein or elsewhere as necessary.
- Viswanathan P, Gupta P, Kapoor S, Gupta S. Thalidomide promotes transplanted cell engraftment in the rat liver by modulating inflammation and endothelial integrity. J Hepatol 2016 Jul 12. pii: S0168-8278(16)30332-4. doi: 10.1016/j.jhep.2016.07.008. [Epub ahead of print]
- Merlin S, Bhargava K, Ranaldo G, Zanolini D, Palestro C, Santambrogio L, Prat M, Follenzi A, Gupta S. Kupffer cell transplantation in mice for elucidating monocyte/macrophage biology and for potential in cell or gene therapy. Am J Pathol 2016 Mar;186(3):539-51. doi: 10.1016/j.ajpath.2015.11.002. Epub 2016 Jan 7. 015 Apr 24.
- Yu Y, Guerrero CR, Liu S, Sharma Y, Gupta S, Wang Y. Comprehensive assessment of oxidatively induced modifications of DNA in a rat model of human Wilson’s disease. Mol Cell Proteomics 2016 Mar;15(3):810-7. doi: 10.1074/mcp.M115.052696. Epub 2015 Sep 11 Jul;100(7):881-92. doi: 10.3324/haematol.2014.123117. Epub 2015 Apr 24.
- Zanolini D, Merlin S, Feola M, Ranaldo G, Amoruso A, Gaidano G, Zaffaroni M, Ferrero A, Brunelleschi S, Valente G, Gupta S, Prat M, Follenzi A. Extra-hepatic sources of FVIII potentially contribute to the coagulation cascade correcting the bleeding phenotype of Hemophilia A mice. Haematologica 2015 Jul;100(7):881-92. doi: 10.3324/haematol.2014.123117. Epub 2015 Apr 24.
- Kumar M, Sharma Y, Bandi S, Gupta S. Endogenous antiviral microRNAs determine permissiveness for hepatitis B virus replication in cultured human fetal and adult hepatocytes. J Med Virol 2015 Jul;87(7):1168-83. doi: 10.1002/jmv.24145. Epub 2015 Feb 17.
- Dogra S, Bandi S, Viswanathan P, Gupta S. Arsenic trioxide amplifies cisplatinum toxicity in human tubular cells transformed by HPV-16 E6/E7 for further therapeutic directions in renal cell carcinoma. Cancer Lett 2015 Jan 28;356(2 Pt B):953-61.
- Viswanathan P, Kapoor S, Kumaran V, Joseph B, Gupta S. Etanercept blocks inflammatory responses orchestrated by TNF-a to promote transplanted cell engraftment and proliferation in rat liver. Hepatology 2014;60:1378-88.
- Kapoor S, Berishvili E, Bandi S, Gupta S. Ischemic preconditioning affects long-term cell fate through DNA damage-related molecular signaling and altered proliferation. Am J Pathol 2014;184:2779-90.
- Bahde R, Kapoor S, Bhargava KK, Palestro CJ, Gupta S. Diagnosis of abnormal biliary copper excretion by positron emission tomography with targeting of (64)Copper-asialofetuin complex in LEC rat model of Wilson's disease. Am J Nucl Med Mol Imaging 2014;4:537-47.
- Bandi S, Viswanathan P, Gupta S. Evaluation of cytotoxicity and DNA damage response with analysis of intracellular ATM signaling pathways. Assay Drug Dev Technol 2014;12:272-81.
- Bahde R, Kapoor S, Gupta S. Nonselective inhibition of prostaglandin-endoperoxide synthases by naproxen ameliorates acute or chronic liver injury in animals. Exp Mol Pathol 2014;96:27-35.
- Bahde R, Kapoor S, Viswanathan P, Spiegel HU, Gupta S. Endothelin-1 receptor A blocker darusentan decreases cell transplantation-induced hepatic perturbations and improves liver repopulation. Hepatology 2014;59:1107-17.
- Kakabadze Z, Gupta S, Pileggi A, Molano RD, Ricordi C, Shatirishvili G, Loladze G, Mardaleishvili K, Kakabadze M, Berishvili E. Correction of diabetes by minimal mass islet transplantation into the small intestinal submucosa. Am J Transplantation 2013;13:2550-57.
- Bahde R, Kapoor S, Bandi S, Bhargava K, Palestro C, Gupta S. Directly acting drugs prostacyclin or nitroglycerine and endothelin receptor blocker bosentan improve cell engraftment in rat liver. Hepatology 2013;57:320-30.
- Follenzi A, Raut S, Merlin S, Sarkar R, Gupta S. Role of bone marrow transplantation for correcting hemophilia A in mice. Blood 2012;119;5532-5542. Editorial commentary: 5344-5346.
- Bandi S, Cheng K, Joseph B, Gupta S. Spontaneous origin from human embryonic stem cells of early developmental stage liver cells displaying conjoint meso-endodermal phenotype with hepatic functions. J Cell Sci 2012;125:1274-83.
- Enami Y, Joseph B, Bandi S, Lin J, Gupta S. Molecular perturbations restrict potential for liver repopulation of hepatocytes isolated from nonheart-beating donor rats. Hepatology 2012;55:1182-92.
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