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，缩短寿命和 损害了生活质量。成人心肌在一年后不能进行再生 心肌梗死激发了使用细胞疗法进行心肌修复的研究。然而，临床试验 DATE显示的益处不大或没有，这表明有必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品提供了有希望的结果，但 移植物一般都是小的，暂时性的，功能益处有限。此外，还有剩余的 关于IPSCs来源的心肌细胞的重要问题，包括最佳输送策略， 免疫原性、成熟度和与天然心肌有效结合的能力而不引起 心律不齐。在这项提案中，三个综合项目将应对这些挑战，并朝着 利用功能性人心脏组织补片(HCTP)修复缺血心肌的长期目标。 第一个项目旨在产生新的细胞群体，包括诱导的心脏前体细胞和 基因工程细胞系将在一种新的人源化小鼠身上评估其免疫原性 模特。这些和其他电池产品，包括商业上可用的资源，将被用于生产 第二个项目中的大血管hCTP。第三个项目将利用猪脑梗塞后模型 通过光学标测技术测试hCTP并优化电和血管整合 和磁共振/核磁共振波谱。这些研究将克服关键障碍，产生大规模、 全功能的人类心脏组织，可以安全地整合到自然心肌中，以提供 治疗晚期缺血性心脏病的强有力的新方法。

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.