Hepatic Progenitor Cell response to ischemia reperfusion injury; biological pathways involved in post-transplant biliary injury and repair

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Liver transplantation is the only therapeutic option available for patients with end stage liver disease. Biliary complications (BC) remain a common source of morbidity and mortality in liver transplant recipients and occur in up to 30% with a mortality rate of 10%. The mechanisms underlying the development of BCs in the setting of liver transplantation remain poorly understood, thus hampering the study of this condition and therapeutic development. During the procurement and transplant process donor organs are exposed to periods of ischemia (insufficient tissue oxygenation due to a restricted blood supply) and reperfusion (restoration of the blood supply after a period of ischemia). The resulting injury is defined as ischemia reperfusion injury (IRI) and in the setting of liver transplantation assumed to be the main cause for the development of postoperative complications such as BCs. A current hypothesis states that IRI results in damage to the Hepatic Progenitor Cell (HPC) population (a subset of cholangiocytes within the biliary tract). Under normal circumstances these HPCs are capable of regenerating both liver and biliary cells following injury. Yet, HPC injury caused by IRI turns them unable to repair the biliary injury, resulting in BC development post liver transplantation. However, this remains to be proven.Work from the Forbes lab has recently found that transplantation of human HPCs (hHPCs) into a murine model of biliary disease enables the human HPCs to engraft into the mouse biliary tree, resulting in biliary regeneration, resolution of biliary strictures, regression of hepatic fibrosis, and a reduction in mortality.The hHPCs have been characterized and cultured as organoids. HPC organoids are an ideal tool to study biliary disease. It has recently been shown that organoid derived bile ducts closely resemble native bile ducts and that HPC organoids retrieved from mice with genetic biliary disorders display structural instability in culture. In the proposed study hHPC organoids will be used to study biliary IRI. The better understanding of the HPC response to IRI and what pathways are involved in biliary regeneration can lead to the development of new therapeutic options for strategies to prevent post-transplant BCs and more widely for cell therapy in general. Available therapeutic or preventive strategies will additionally allow for re-definition of acceptance criteria for liver grafts resulting in higher acceptance rates which in turn will lower waitlist mortality. The study will be conducted at the MRC Centre for Regenerative Medicine of the University of Edinburgh.