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

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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.