Liver-directed cell/gene therapy is of enormous significance for many genetic, metabolic and acquired conditions that may cause injury and/or adverse effects in the liver or multiple other target organs. Based on work in our and other laboratories over the past 25 years, hepatocyte transplantation has been performed in some 100 people with various conditions. These studies indicated that insights from rodent models were appropriate and predicted clinical outcomes in people after cell/gene therapy. Moreover, initial experiences of cell therapy in people established the need for returning to studies in animals, particularly to define mechanisms in engraftment of transplanted cells that could advance liver repopulation to achieve superior therapeutic outcomes. In more recent studies, it was shown that transplanted cells engrafted in the liver through multi-step processes. For instance, after deposition in liver sinusoids, transplanted hepatocytes engrafted in liver parenchyma, whereas after injection into the hepatic artery, transplanted hepatocytes were promptly destroyed. Entry of transplanted cells in the liver parenchyma required disruption of sinusoidal endothelial barrier, so that cells could travel through the space of Disse, followed by liver remodeling to accept transplanted cells in the parenchymal structure. However, cell transplantation induced ischemia and tissue injury, leading to recruitment of inflammatory cells in the setting of syngeneic or autologous cells, and of professional immunocytes, in the setting of allogeneic cells, along with activation of liver sinusoidal endothelial cells and hepatic stellate cells. Cell-cell interactions in the liver could be beneficial, e.g., disruption of liver sinusoidal endothelial cells improved engraftment of transplanted cells and beneficial activation of hepatic stellate cells released cytoprotective factors and promoted matrix remodeling, again with superior cell engraftment. Or cell-cell interactions could be deleterious. For instance, release of inflammatory cytokines and chemokines resulted in clearance of significant fractions of transplanted cells over several hours, while activation of additional adaptive immune responses against allogeneic cells, led to the clearance of cells over several days. As suitable interventions could alter these initial cell losses, we will address the hypothesis that insights into mechanisms of cell transplantation-induced liver inflammation and its effects on cell engraftment will help obtain effective pharmacological approaches for advancing cell/gene therapy. To understand the nature of cellular perturbations, we will perform studies in superb rodent models and define inflammatory cell-specific changes, including mechanisms in relevant cytokine-chemokine activations, as well as cell-cell interactions. We will perform pharmacological studies with clinically-relevant drugs to block undesirable mechanisms for improving engraftment of transplanted cells. Moreover, we will examine the efficacy of these manipulations for liver repopulation and cell therapy in further animal models. Taken together, this proposal will advance novel insights for liver-directed cell/gene therapy and will be of extensive significance for human health.
Recent insights into organ repopulation with tissue-derived or exogenous cells continue to foster interest in cell therapy (1-3). Based on significant amount of animal work, some 100 people have been treated with hepatocyte transplantation, including for liver failure, chronic liver disease, genetic disorders, and other conditions (1, 2). Liver-directed cell therapy is relevant for multiple disorders, including those listed in Table 1. A major benefit of cell therapy is that this Table 1 could help in overcoming shortages of donor organs in important ways, since cells Candidate conditions for liver-directed cell therapy isolated from a single donor organ could be utilized for multiple recipients. This would include people who may otherwise be treated with orthotropic liver transplantation (OLT). Moreover, cell therapy will be far less complex and expensive compared with OLT. However, although cells can be safely transplanted, much more work is needed to define how the extent of liver repopulation with cells may be improved. As most cells are rapidly destroyed after transplantation into the liver, preventing this cell loss to enhance engraftment, survival, function and proliferation of transplanted cells will markedly improve clinical outcomes. These principles must be translated in disease- specific settings. In many instances, animal models faithfully reproduce important aspects of disorders in people, e.g., Wilson's disease, where copper toxicosis causes progressive liver damage, including hepatic fibrosis and liver failure, which are also encountered in chronic viral hepatitis. In this way, insights into mechanisms of liver repopulation with healthy cells in chronic liver disease will benefit consideration of cell/gene therapy approaches in hepatitis. As viral hepatitis B and C alone afflict over 300 million people worldwide, and significant fractions of those people will suffer from acute or chronic liver failure, cell/gene therapy could be potentially helpful for many more people. Therefore, critical insights in liver-directed cell/gene therapy will be very important for human health.
|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|
|Yu, Yang; Guerrero, Candace R; Liu, Shuo et al. (2016) Comprehensive Assessment of Oxidatively Induced Modifications of DNA in a Rat Model of Human Wilson's Disease. Mol Cell Proteomics 15:810-7|
|Merlin, Simone; Bhargava, Kuldeep K; Ranaldo, Gabriella et al. (2016) Kupffer Cell Transplantation in Mice for Elucidating Monocyte/Macrophage Biology and for Potential in Cell or Gene Therapy. Am J Pathol 186:539-51|
|Zanolini, Diego; Merlin, Simone; Feola, Maria et al. (2015) Extrahepatic sources of factor VIII potentially contribute to the coagulation cascade correcting the bleeding phenotype of mice with hemophilia A. Haematologica 100:881-92|
|Dogra, Samriti; Bandi, Sriram; Viswanathan, Preeti et al. (2015) Arsenic trioxide amplifies cisplatin toxicity in human tubular cells transformed by HPV-16 E6/E7 for further therapeutic directions in renal cell carcinoma. Cancer Lett 356:953-61|
|Kumar, Mukesh; Sharma, Yogeshwar; Bandi, Sriram et al. (2015) Endogenous antiviral microRNAs determine permissiveness for hepatitis B virus replication in cultured human fetal and adult hepatocytes. J Med Virol 87:1168-83|
|Kapoor, Sorabh; Berishvili, Ekaterine; Bandi, Sriram et al. (2014) Ischemic preconditioning affects long-term cell fate through DNA damage-related molecular signaling and altered proliferation. Am J Pathol 184:2779-90|
|Gupta, Sanjeev (2014) Cell therapy to remove excess copper in Wilson's disease. Ann N Y Acad Sci 1315:70-80|
|Viswanathan, Preeti; Kapoor, Sorabh; Kumaran, Vinay et al. (2014) Etanercept blocks inflammatory responses orchestrated by TNF-Î± to promote transplanted cell engraftment and proliferation in rat liver. Hepatology 60:1378-88|
|Bahde, Ralf; Kapoor, Sorabh; Gupta, Sanjeev (2014) Nonselective inhibition of prostaglandin-endoperoxide synthases by naproxen ameliorates acute or chronic liver injury in animals. Exp Mol Pathol 96:27-35|
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