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

肝移植是终末期肝病患者的唯一治疗选择。胆道并发症（BC）仍然是肝移植受者发病率和死亡率的常见来源，发生率高达30%，死亡率为10%。在肝移植背景下BC发展的潜在机制仍然知之甚少，从而阻碍了对这种情况和治疗发展的研究。在获取和移植过程中，供体器官暴露于缺血（由于血液供应受限导致组织氧合不足）和再灌注（在缺血一段时间后恢复血液供应）的时期。由此产生的损伤被定义为缺血再灌注损伤（IRI），并且在肝移植的情况下被认为是术后并发症如BC发展的主要原因。目前的假设指出，IRI导致肝祖细胞（HPC）群（胆道内胆管细胞的一个子集）受损。在正常情况下，这些HPC能够在损伤后再生肝细胞和胆细胞。然而，IRI引起的HPC损伤使它们无法修复胆道损伤，导致肝移植后BC的发展。然而，这仍有待证实。最近，福布斯实验室的工作发现，将人HPC（hHPC）移植到胆道疾病的小鼠模型中，使人HPC能够移植到小鼠胆道树中，导致胆道再生，胆道狭窄的解决，肝纤维化的消退和死亡率的降低。hHPC已被表征和培养为类器官。HPC类器官是研究胆道疾病的理想工具。最近已经表明，类器官衍生的胆管与天然胆管非常相似，并且从患有遗传性胆道疾病的小鼠中检索的HPC类器官在培养中显示出结构不稳定性。在拟定研究中，hHPC类器官将用于研究胆汁IRI。更好地了解HPC对IRI的反应以及胆道再生涉及哪些途径，可以为预防移植后BC的策略和更广泛的细胞治疗提供新的治疗选择。可用的治疗或预防策略还将允许重新定义肝移植的接受标准，从而提高接受率，进而降低等待名单死亡率。这项研究将在爱丁堡大学MRC再生医学中心进行。

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.