Experimental models with specific approaches to augment human fetal liver cell engraftment

Abstract

Experimental models with specific approaches to augment human fetal liver cell engraftment

Pradeep Patil Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy at University of Gothenburg

Background: Liver disease is a common cause of morbidity and mortality worldwide. Orthotopic liver transplantation has so far been the only available therapy for patients with end-stage liver failure. Unfortunately, the availability of donor organs is limited and more than 40% of patients become too sick to survive each year while waiting for liver transplants. Cellular therapy with stem cells and their progeny is a promising new approach to this largely unmet medical need, but is yet to be integrated into the current clinical system. Impediments in cell transplantation are well characterized, but there is lack of reliable solutions, which has limited the use of this technique to act as a bridge (temporary support) to transplantation. Aims: Studies covered under the current thesis are focused on validation and evaluation of reliable cell sources and feasible protocols for enhancing their engraftment and proliferation in animal models. Materials and methods: The mammalian fetal liver contains colony-forming cells with high proliferative potential. The use of human fetal liver cells (hFLCs) is a suitable candidate for the purpose of cell therapy and diagnostics. We have evaluated hFLCs lines as a potential source of stem cells and tested their in vivo functions in a model of liver injury using nude mouse. Results and discussion: This thesis has shown that the regimens of preconditioning (using chemokines) or the co-transplantation (liver cells with mesenchymal stem cells) have the possibility to augment engraftment. Also, manipulating liver cells ex vivo to increase longevity helps in growing cell colonies much faster for many passages to produce a limitless population. It also demonstrates a novel marker to isolate adult or fetal liver stellate cells, which has an important role in immunoregulation and liver fibrosis. Summary: This thesis describes and highlights novel and feasible approaches in liver cell transplantation, with the possibility to improve current clinical protocols.

Keywords: cell transplantation, chemokines, SV40, stellate cell, MSCs