Cellular interactions underpinning the anti-inflammatory action of Mesenchymal Stromal Cells in Donation after Cardiac Death liver injury

慢性肝病影响了大约1%的英国人口，是前五名中唯一的死亡原因，而且仍在逐年增加，每年有近12，00人死于肝功能衰竭。肝移植是唯一有效的治疗方法，但等待名单很长，成年人的平均时间为142天，儿童的平均时间为78天。由于捐赠器官的数量无法满足目前的高需求，一些中心进行了心脏死亡(DCD)移植后的捐赠。与脑干死亡相比，这些患者的供体肝脏由于心源性死亡后的缺氧而受到了更大的侮辱。这会激活免疫系统，导致肝脏受损，导致国际电信联盟长期停留，在某些情况下可能导致新肝脏衰竭。间充质基质细胞(MSC)是一种功能强大的细胞，已被证明可以减少免疫系统造成的损害，如类风湿性关节炎和移植物抗宿主病等免疫系统攻击组织的疾病。这笔赠款的目的是证明MSC能够在类似于DCD肝移植的模型中减少损害。尽管最近的发现表明，MSC可以在不迁移到靶器官的情况下远程发挥作用，但它们可以聚集在活跃的炎症区域并发挥作用。此外，注射包裹在藻酸盐涂层中的MSC可以延长这些细胞的寿命和活性。我的研究项目将使用小鼠肝损伤模型来验证MSC可以用于减轻DCD肝移植后的损伤的假设。我还会看看这种有益的效果是否会受到细胞管理方式的影响。具体地说，我会看看包裹在特殊聚合物中的MSC是否更有效。这一点很重要，因为这表明它们可以在不迁移到受伤的肝脏的情况下发挥部分作用。使用最先进的细胞跟踪技术，我将尝试跟踪MSC的分布和数量，并找出它们在哪里发挥作用。我将通过修改MSC来实现后者，使它们在积极减少炎症时发出荧光。然后，我将尝试并确定MSC是否通过体内的一种中间类型的细胞(髓系来源的抑制细胞)发挥其有益的作用。这可能解释了当MSC被包裹而不能迁移到损伤器官时是如何起作用的。本研究获得的知识将有助于理解MSC是如何发挥其作用的。它还将决定最有效的管理途径。可能将其转化为临床试验的目的是改善DCD移植的结果，并降低移植患者的风险。

Chronic liver disease effects approximately 1% of the UK population and is the only cause of death in the top 5 that is still increasing year on year with nearly 12,00 deaths per year due to liver failure. Liver transplantation is the only effective treatment but waiting lists are long, the average time for an adult being 142 days, and a child 78 days. Because of the high demand which cannot currently be met by the number of organs donated, donation after cardiac death (DCD) transplantation is carried out in some centres. The donor liver from these patients has had a much greater insult due to the lack of oxygen following cardiac death as compared to brainstem death. This activates the immune system resulting in damage to the liver, leading to a prolonged ITU stay, and can in cases lead to failure of the new liver. Mesenchymal stromal cells (MSC) are powerful cells that have been shown to reduce the damage that the immune system causes, as demonstrated in other conditions such as rheumatoid arthritis and graft versus host disease where the immune system attacks tissues. The purpose of this grant is to demonstrate that MSC are able to reduce damage in models that are similar to DCD liver transplant. MSC can home to areas of active inflammation and exert their effect, although recent discoveries indicate that they may be able to exert their effect remotely without migrating to the target organ. Moreover, injection of MSC encapsulated in an alginate coating can prolong the life span and activity of these cells.My research project will use mouse models of liver injury to test the hypothesis that MSC can be used to reduce the damage seen after DCD liver transplant. I will also look to see if this beneficial effect is affected by how the cells are administered. Specifically I will look to see if MSC encapsulated in special polymers are more effective. This is important as it would suggest they can exert a part of their effect without migrating to the injured liver.Using state of the art cell tracking technology I will attempt to track the distribution and number of MSC as well as working out where they are exerting their actions. I will achieve the latter by modifying the MSC such that they fluoresce when they are actively reducing inflammation. I will then try and establish if MSC are exerting their beneficial effects by acting through an intermediary type of cell in the body (myeloid derived suppressor cells). This might explain how MSC have been act to when they have been encapsulated and not been able to migrate to the injured organThe knowledge gained during this research will aid the understanding of how MSC exert their effect. It will also determine the most effective route of administration. The possible translation of this into clinical trials would aim to improve the outcomes from DCD transplantation and reduce the risk to the transplant patient.