Integrated Cellular and Tissue Engineering for Ischemic Heart Disease

摘要 缺血性心脏病继续对公众健康产生巨大影响，缩短寿命， 损害生活质量。成年人心肌在缺血后不能再生， 心肌梗塞激发了使用细胞疗法进行心肌修复的研究。然而，临床试验， 迄今为止，已经显示出有限的益处或没有益处，这表明需要考虑其他细胞来源和方法。 在大型动物模型中，人类多能干细胞的衍生物提供了有希望的结果，但 移植物通常是小的、短暂的并且功能益处有限。此外，还有 关于来自iPSC的心脏细胞的重要问题，包括最佳递送策略， 免疫原性、成熟度和有效偶联天然心肌而不引起心肌细胞凋亡的能力。 心律不齐在本提案中，三个综合项目将应对这些挑战，并朝着 长期目标是利用功能性人类心脏组织补片（hCTP）修复缺血心肌。 第一个项目旨在产生新的细胞群，包括诱导的心脏祖细胞和 将在新型人源化小鼠中评价其免疫原性的基因工程细胞系 模型这些和其他细胞产品，包括市售来源，将用于产生 在第二个项目中使用大血管化的hCTP。第三个项目将利用猪梗死后模型 测试hCTP并优化通过光学标测技术评估的电和血管整合 和MRI/NMR光谱。这些研究将克服关键障碍， 能够安全地整合到天然心肌中的功能完整的人类心脏组织， 治疗晚期缺血性心脏病的新方法。

ABSTRACT Ischemic heart disease continues to have a tremendous impact on public health, shortening lifespan and impairing the quality of life. The inability of the adult human myocardium to undergo regeneration after a myocardial infarction has inspired research using cell therapy for myocardial repair. However, clinical trials to date have shown modest or no benefit, suggesting the need to consider other cell sources and approaches. In large animal models, derivatives of human pluripotent stem cells have provided promising results, but the grafts have generally been small, transient, and of limited functional benefit. In addition, there remain important questions regarding cardiac cells derived from iPSCs, including the optimal delivery strategy, immunogenicity, maturity, and the ability to couple effectively to the native myocardium without causing arrhythmias. In this proposal, three integrated projects will address these challenges and advance toward the long-term goal of utilizing a functional human cardiac tissue patch (hCTP) for repair of ischemic myocardium. The first project aims to generate novel cell populations, including induced cardiac progenitor cells and genetically engineered cell lines that will be evaluated for their immunogenicity in a novel humanized mouse model. These and other cell products, including commercially available sources, will be utilized to generate large vascularized hCTPs in the second project. The third project will utilize a porcine post-infarction model to test hCTPs and optimize electrical and vascular integration as assessed by optical mapping technology and MRI/NMR spectroscopy, respectively. These studies will overcome critical barriers to generating large, fully functional human cardiac tissues that can be integrated safely into the native myocardium to provide a powerful new approach for treatment of advanced ischemic heart disease.