Transplantation of hearts from donation after circulatory death

循环死亡后捐献的心脏移植

• 批准号: 10636155
• 负责人: Meijing Wang
• 金额: $ 43.03万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-15 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10636155
• 关键词: Acute; Adoption; Animal Model; Attention; Cardiac; Cardiac Myocytes; Cardiopulmonary Resuscitation; Cell secretion; Cessation of life; Circadian Rhythms; Clinical; Clinical Trials; Conditioned Culture Media; Cryopreservation; Data; Data Analyses; Deterioration; Devices; Donor person; Engineering; Family suidae; Foundations; Generations; Genes; Goals; Health; Heart; Heart Transplantation; Heart failure; Homeostasis; Human; Impairment; Infusion procedures; Injury; Ischemia; Knockout Mice; Life; Mediating; Mesenchymal Stem Cells; Metabolic; Mitochondria; Modality; Mus; Muscle Cells; Myocardial; Myocardial Ischemia; Myocardium; Organ; Organ Viability; Outcome; Patients; Performance; Perfusion; Process; Proteins; Publishing; Recovery; Recovery Support; Recovery of Function; Regulation; Reperfusion Injury; Reperfusion Therapy; Reporting; Resources; Resuscitation; Role; Source; Stress; Structure; Testing; Therapeutic; Therapeutic Agents; Therapeutic Uses; Time; Translating; Transplantation; Treatment Efficacy; Warm Ischemia; Work; bone marrow mesenchymal stem cell; cardiac repair; extracellular vesicles; graft function; heart function; heart preservation; improved; improved outcome; in vivo; insight; ischemic injury; knock-down; myocardial damage; myocardial injury; novel strategies; paracrine; post-transplant; pre-clinical; preservation; prevent; protective factors; repaired; stem cells; therapeutic target; transcriptome; transcriptome sequencing; translational potential; transplant model

Heart transplantation (HTx) is the ultimate treatment for end-stage heart failure, but its use is limited by the availability of donor hearts. As a result, a substantial number of HTx candidates die awaiting transplant. Donation after circulatory death (DCD) offers a promising additional source for HTx. However, its adoption is hindered due to obligatory warm ischemic injury during death process and subsequent reperfusion injury, as well as unsuitable preservation modality during transport. The EVHP provides normothermic perfusion platform for satisfactory preservation of DCD hearts and offers the possibility to deliver therapeutic agents that improve resuscitation of DCD hearts prior to transplantation. Given stem cell-derived paracrine protection following myocardial ischemia, our goal is to determine potential efficacy of post-ischemic administration of stem cell secretions (conditioned medium [CM], extracellular vesicles [EVs], or engineered EVs) using the EVHP on recovery of DCD hearts prior to transplantation, thereby increasing the number of available donor hearts. Our recent studies have reported that adding MSC-CM or MSC-EVs to storage solution protected heart graft performance after 6h-cold storage using an in vivo mouse HTx model and MSC-CM restored cold ischemia- impaired cardiac transcriptome profile. These results suggest therapeutic potential of MSC secretions on donor heart preservation. Our published work and preliminary data have also shown: 1) using human MSCs or their CM improved heart functional recovery in the EVHP following acute ischemia/reperfusion (I/R); 2) MSC-CM prevented mitochondrial damage in donor hearts from cold ischemia and restored clock gene period 2 (Per2, with a role in mitochondrial metabolic regulation); 3) warm ischemia resulted in abnormal mitochondrial structure in mouse and human DCD hearts, with decreased Per2, and 4) Per2 knockdown worsened mitochondrial injury and abolished MSC CM-mediated mitochondrial preservation in myocytes during stress. Collectively, we hypothesize that post-ischemic administration of MSC secretions using the EVHP ameliorates warm ischemia-induced functional deterioration of DCD hearts via Per2-elicited mitochondrial improvement. We expect that a novel approach using the engineered EVs to deliver Per2 will promote mitochondrial recovery and myocardial resuscitation in DCD hearts. We propose two aims: 1. test the hypothesis that ex vivo application of MSC secretions using the EVHP ameliorates warm ischemia-induced myocardial damage via mitochondrial preservation in DCD hearts; and 2. determine the role of Per2 in improving mitochondrial performance in DCD hearts and demonstrate beneficial effects of Per2-loaded MSC-EVs on resuscitation of DCD hearts. The translational potential of MSC-derived therapy and the engineered EVs will also be assessed in human-like porcine DCD hearts. The results from this study can provide foundation for potential clinical trials in that MSC secretions can be utilized to improve DCD heart recovery and help us gain mechanistic insights on therapeutic targets to limit warm ischemic injury in DCD hearts for transplantation.

心脏移植（HTX）是终极心力衰竭的最终治疗方法，但其使用受到限制 供体心的可用性。结果，大量的HTX候选者正在等待移植。 循环死亡后的捐赠（DCD）为HTX提供了有希望的其他来源。但是，它的采用是 由于强制性温暖的缺血性损伤而受到阻碍 以及运输过程中不合适的保存方式。 EVHP提供了常规灌注平台 为了满足DCD心脏的保存，并提供了提供改善治疗剂的可能性 在移植之前对DCD心脏的复苏。给定干细胞衍生的旁分泌保护以下 心肌缺血，我们的目标是确定干细胞缺血后给药的潜在功效 分泌物（条件培养基[CM]，细胞外囊泡[EVS]或工程EVS）使用EVHP ON 在移植之前恢复DCD心脏，从而增加了可用的供体心脏的数量。我们的 最近的研究报告说，将MSC-CM或MSC-EV添加到存储溶液保护心脏移植 使用体内小鼠HTX模型和MSC-CM恢复冷缺血后的6小时存储后的性能 心脏转录组概况受损。这些结果表明MSC分泌在供体上的治疗潜力 心脏保存。我们发表的工作和初步数据也显示了：1）使用人类MSC及其 急性缺血/再灌注后，CM改善了EVHP的心脏功能恢复（I/R）； 2）MSC-CM 防止供体心脏中的线粒体损害冷缺血并恢复时钟基因2（PER2， 在线粒体代谢调节中起作用）； 3）温暖的缺血导致线粒体异常 小鼠和人类DCD心脏的结构，PER2降低，4）PER2敲低恶化 在压力期间，线粒体损伤和消除了肌细胞中的MSC CM介导的线粒体保存。 总的来说，我们假设使用EVHP改善MSC分泌的缺血后给药 通过PER2精选的线粒体改善，缺血性缺血诱导的DCD心脏的功能恶化。 我们希望使用工程的电动汽车传递PER2的一种新颖的方法将促进线粒体 DCD心脏中的恢复和心肌复苏。我们提出了两个目的：1。检验了离体的假设 使用EVHP施用MSC分泌物，可以通过 DCD心脏中的线粒体保存；和2。确定PER2在改善线粒体中的作用 DCD心脏的表现，并表现出PER2负载的MSC-EV对复兴的有益影响 DCD心。 MSC衍生的疗法和工程EV的转化潜力也将被评估 在类似人类的猪DCD心中。这项研究的结果可以为潜在的临床试验提供基础 因为MSC分泌可以用于改善DCD心脏恢复并帮助我们获得机械见解 治疗靶标限制DCD心脏中温暖的缺血性损伤进行移植。