目的:心脏损伤后,内源性修复机制无效。然而,基于细胞的疗法提供了一种有希望的临床干预措施,其基于其旁分泌因子恢复和重塑受损心肌的能力。最近的临床试验表明,成人心脏来源的细胞疗法对于治疗缺血性心力衰竭是安全的,虽然再生潜力有限。心肌梗死后心球衍生细胞的有限效率是由于其分泌组的质量较差。本研究旨在通过调节缺氧诱导因子-1α来增强心肌来源细胞的治疗潜力。旁分泌因子的调节器。
方法:从接受心脏手术的患者的右心耳活检中分离并扩增心球来源的细胞。研究缺氧诱导因子-1α对分泌组的影响,用缺氧诱导因子-1α过表达的慢病毒转导心球来源的细胞,使用酶联免疫吸附测定对分泌组中的各种心脏保护因子进行定量。在大鼠心肌梗死模型中对心球来源的细胞的再生潜能进行比较分析。
结果:机械,缺氧诱导因子-1α在成人心球来源细胞中的过度表达导致分泌组富含血管内皮生长因子A,血管生成素1,基质细胞衍生因子1α,和碱性成纤维细胞生长因子.心肌梗死后心肌内给予缺氧诱导因子-1α转导的心球来源细胞显著改善左心室射血分数,分数缩短,左心室收缩末期容积,和心输出量.大鼠心脏的功能改善与通过增强的血管生成和减少的心肌纤维化改善的梗死心肌的适应性重塑相关。我们还表明,缺氧诱导因子-1α在心肌来源的细胞中的表达受到衰老的不利影响。
结论:缺氧诱导因子-1α通过富集心球来源的细胞分泌体与心脏保护因子,提高了心球来源的细胞保护心肌梗死后心肌功能的功能潜能。该策略可用于在未来的临床试验中提高基于异体细胞的疗法的功效。
After cardiac injury, endogenous repair mechanisms are ineffective. However, cell-based therapies provide a promising clinical intervention based on their ability to restore and remodel injured myocardium due to their paracrine factors. Recent clinical trials have demonstrated that adult cardiosphere-derived cell therapy is safe for the treatment of ischemic heart failure, although with limited regenerative potential. The limited efficiency of cardiosphere-derived cells after myocardial infarction is due to the inferior quality of their secretome. This study sought to augment the therapeutic potential of cardiosphere-derived cells by modulating hypoxia-inducible factor-1α, a regulator of paracrine factors.
Cardiosphere-derived cells were isolated and expanded from the right atrial appendage biopsies of patients undergoing cardiac surgery. To study the effect of hypoxia-inducible factor-1α on the secretome, cardiosphere-derived cells were transduced with hypoxia-inducible factor-1α-overexpressing lentivirus, and various cardioprotective factors within the secretome were quantified using enzyme-linked immunosorbent assays. Comparative analysis of the regenerative potential of cardiosphere-derived cells was performed in a rat myocardial infarction model.
Mechanistically, overexpression of hypoxia-inducible factor-1α in adult cardiosphere-derived cells led to the enrichment of the secretome with vascular endothelial growth factor A, angiopoietin 1, stromal cell-derived factor 1α, and basic fibroblast growth factor. Intramyocardial administration of cardiosphere-derived cells transduced with hypoxia-inducible factor-1α after myocardial infarction significantly improved left ventricular ejection fraction, fractional shortening, left ventricular end-systolic volume, and cardiac output. Functional improvement of the rat heart correlated with improved adaptive remodeling of the infarcted myocardium by enhanced angiogenesis and decreased myocardial fibrosis. We also showed that hypoxia-inducible factor-1α expression in cardiosphere-derived cells was adversely affected by aging.
Hypoxia-inducible factor-1α improves the functional potency of cardiosphere-derived cells to preserve myocardial function after myocardial infarction by enriching the cardiosphere-derived cells\' secretome with cardioprotective factors. This strategy may be useful for improving the efficacy of allogeneic cell-based therapies in future clinical trials.