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

细胞相互作用支撑间充质基质细胞在心脏死亡肝损伤后捐赠中的抗炎作用

• 批准号: MR/L017261/1
• 负责人: Andrew Owen
• 金额: $ 32.29万
• 依托单位: University of Birmingham
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FL017261%2F1
• 关键词: Cellular; interactions; underpinning; anti; inflammatory

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.

慢性肝病影响了大约1%的英国人口，是前5名中唯一一个仍在逐年增加的死亡原因，每年有近1.2万人死于肝功能衰竭。肝移植是唯一有效的治疗方法，但等待的时间很长，成人的平均时间为142天，儿童为78天。由于目前捐赠的器官数量无法满足高需求，一些中心开展了心脏死亡后捐赠（DCD）移植。与脑干死亡相比，由于心脏死亡后缺氧，这些患者的供体肝脏受到了更大的损害。这会激活免疫系统，导致肝脏受损，导致ITU停留时间延长，并在某些情况下导致新肝脏衰竭。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，如在类风湿关节炎和移植物抗宿主病等免疫系统攻击组织的其他疾病中。这项拨款的目的是证明MSC能够减少与DCD肝移植相似的模型的损伤。虽然最近的发现表明MSC可以在不迁移到靶器官的情况下远程发挥作用，但MSC可以回到活动性炎症区域并发挥其作用。此外，注射海藻酸盐包被的间充质干细胞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可以减少DCD肝移植后损伤的假设。我还将观察这种有益效果是否受到细胞施用方式的影响。具体来说，我将看看在特殊聚合物中封装的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损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，我将尝试确定MSC是否通过体内一种中间类型的细胞（髓源性抑制细胞）发挥其有益作用。这也许可以解释当MSC被封装并且无法迁移到受伤器官时，它们是如何起作用的。在本研究中获得的知识将有助于理解MSC如何发挥其作用。它还将确定最有效的行政管理途径。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。

项目成果

How fast is too fast? Chest compression rate revisited from a new perspective.

多快才算太快呢？

• DOI: 10.1016/j.resuscitation.2016.10.009
• 发表时间: 2017
• 期刊: Resuscitation
• 影响因子: 6.5
• 作者: Alderman JE

Antiviral prophylaxis inhibits cytomegalovirus reactivation in critical illness.

抗病毒预防可抑制危重疾病中巨细胞病毒的再激活。

• 发表时间: 2015
• 作者: Cowley N

COVID-19 recovery: potential treatments for post-intensive care syndrome.

• DOI: 10.1016/s2213-2600(20)30457-4
• 发表时间: 2020-11
• 期刊: The Lancet. Respiratory medicine
• 作者: Bangash MN;Owen A;Alderman JE;Chotalia M;Patel JM;Parekh D
• 通讯作者: Parekh D

Mesenchymal stromal cell therapy in liver disease: opportunities and lessons to be learnt?

• DOI: 10.1152/ajpgi.00036.2015
• 发表时间: 2015-11-15
• 期刊: American journal of physiology. Gastrointestinal and liver physiology
• 作者: Owen A;Newsome PN
• 通讯作者: Newsome PN

A novel way to promote mass public engagement in CPR education.

促进公众参与心肺复苏术教育的新颖方式。

• DOI: 10.1016/j.resuscitation.2016.09.030
• 发表时间: 2016
• 期刊: Resuscitation
• 影响因子: 6.5
• 作者: Owen A