Autogeneic Mitochondria: Surgical Cardioprotection

描述（申请人提供）：细胞疗法在心肌修复或再生方面显示出巨大的潜力；然而，关于特定细胞群的功效、细胞收获和扩增的物流、基于细胞的心肌修复/再生机制的争论仍有待阐明。最重要的是，在细胞分离、免疫耐受、细胞植入和整合方面仍然存在困难。因此，增强细胞递送、细胞功能/存活的策略对于通过细胞治疗成功修复/再生心肌至关重要。最近，我们已经证明，从患者自身的骨骼组织中分离出不受缺血影响的自生线粒体，然后在早期再灌注时注入缺血区，可显著减少肌坏死（坏死和凋亡），并显著增强缺血后的功能。移植的线粒体存活，呼吸能力强，维持膜电位，在注射后至少21天内存在于心肌中，并在距注射部位相当远的地方从外膜分布到心内膜下。从远端骨骼肌中分离和制备自源线粒体是快速的，可以在< 90分钟内完成，这一时间框架在冠状动脉搭桥术（CABG）和经皮冠状动脉介入治疗ST段抬高型心肌梗死（PCI-STEMI）的冠状动脉血运重建术的临床干预措施中是合理的。自体线粒体移植为实际应用提供了免疫学上的优势，无需使用抗排斥药物治疗，可以作为一种排他性干预，也可以作为随后的自体、同种或异种细胞再生干预之前的主要干预，以改善肌坏死和增强心肌功能。我们建议在临床相关的原位冠脉搭桥和PCI-STEMI模型中优化使用自体线粒体移植来改善肌坏死和增强心肌功能；并通过生化/免疫组织化学、核磁共振和综合转录组学和蛋白质组学分析，确定自体线粒体移植显著增强手术心脏保护的具体机制。

DESCRIPTION (provided by applicant): Cell-based therapies for myocardial repair or regeneration have shown great potential; however, debate as to the efficacy of specific cell populations, the logistics of cell harvesting and expansion, the mechanisms of cell- based myocardial repair/regeneration remain to be elucidated. Most importantly difficulties over cell isolation, immune tolerance, cellular engraftment and integration remain. Therefore strategies to augment cell delivery, cell function/survival are crucial in permitting successful myocardial repair/regeneration through cellular therapy. Recently, we have demonstrated that autogeneic mitochondria isolated from the patient's own body, from skeletal tissue, unaffected by ischemia and then injected into the ischemic zone during early reperfusion significantly decreases myonecrosis (necrosis and apoptosis) and significantly enhance post-ischemic function. The transplanted mitochondria are viable, respiration competent, maintain membrane potential, are present in the myocardium for at least 21 days after injection and are distributed from the epi- to the sub- endocardium at significant distance from the site of injection. The isolation and preparation of autogeneic mitochondria from remote skeletal muscle is rapid and can be performed in < 90 min. - a time frame reasonable within the clinical interventions of both coronary artery bypass grafting (CABG) and percutaneous coronary intervention for coronary revascularization for ST segment elevation myocardial infarction (PCI-STEMI). Autogeneic mitochondrial transplantation provides immunological advantages for practical application without the use of anti-rejection drug therapy and could be used either as an exclusive intervention or as a primary intervention prior to subsequent auto-, allo- or xeno-geneic cellular regenerative interventions to ameliorate myonecrosis and enhance myocardial function. We propose to optimize the use of autogeneic mitochondrial transplantation for the amelioration of myonecrosis and enhancement of myocardial function in the clinically relevant in situ CABG and PCI-STEMI model; and to identify the specific mechanism(s) through which autogenic mitochondrial transplantation significantly enhances surgical cardioprotection using biochemical /immunohistochemical, NMR and integrated transcriptomic and proteomic analysis.