Strategies to Enhance Engineered Heart Tissue Based Myocardial Repair

项目总结 缺血性心脏病，如不稳定的冠状动脉心绞痛或心肌梗死，通常会导致心脏收缩 由于收缩的心肌细胞丢失而导致的衰竭。工程化心脏组织介导的干细胞移植 细胞来源的心肌细胞具有再生心肌和改善心功能的前景 临床前动物模型中的心肌梗死后。尽管有这些令人鼓舞的结果，但几个关键的 障碍限制了工程化心脏组织治疗的临床应用。例如，血液灌注率低 在梗死区损害移植的心肌细胞的存活。此外，程序还包括 工程心脏组织的移植通常需要开胸手术，这是一个巨大的挑战 严重心力衰竭的患者。我们之前研究的数据显示，促进细胞周期和 人诱导多能干细胞(hiPSC-CMS)的增殖是增强 缺血性心脏病的植入和功能恢复。我们还产生了一种新型的纳米颗粒 通过增加缺血心脏的血管生成来保护心肌。此外，我们 建立了一种可注射和形状可恢复的组织与凝胶涂覆的纳米纤维支架。在这个项目中， 我们的目标是开发新的方法，通过整合来增强植入的HiPSC-CMS的植入 纳米材料、细胞和组织工程技术。具体地说，我们将开发一种新型的工程 心脏组织，利用纳米材料的能力释放促血管生成分子并促进 在这些工程心脏组织和梗塞心脏中进行血管重建；2)利用我们的 最近建立的诱导工程化心脏内存活心肌细胞增殖的方案 组织；以及3)研究是否将这些新的工程心脏组织输送给患有急慢性心脏病的动物 心肌梗死导致强大的心肌再生和修复。

PROJECT SUMMARY Ischemic heart disease, such as unstable coronary angina or myocardial infarction, often leads to systolic heart failure due to the loss of contractile cardiomyocytes. Engineered heart tissue mediated transplantation of stem cell derived cardiomyocytes holds the promise to regenerate the myocardium and improve cardiac function post myocardial infarction in preclinical animal models. Despite these encouraging results, several critical barriers limit the clinical application of engineered heart tissue-based therapy. For example, the poor perfusion in the infarct area compromises the survival of transplanted cardiomyocytes. In addition, the procedure of transplantation of engineered heart tissue typically requires open chest surgery which is a significant challenge to the patients with severe heart failure. Data from our previous studies showed that promoting cell cycle and proliferation in human induced pluripotent stem cells (hiPSC-CMs) constitutes a viable approach to enhance engraftment and restore function in ischemic heart disease. We also generated a new type of nanoparticles that enable myocardial protection via increased vasculogenesis in the ischemic heart. Furthermore, we established an injectable and shape-recoverable tissue with GelMA-coated nanofiber scaffolds. In this project, we aimed to develop novel approaches to enhance the engraftment of implanted hiPSC-CMs via integrating nanomaterials, cell- and tissue-engineering technologies. Specifically, we will 1) develop a novel engineered heart tissue which leverages the capacity of nanomaterials to release pro-vasculogenic molecules and promote revascularization in these engineered heart tissues and in the infarct heart; 2) take the advantage of our recently established protocol to induce the proliferation of survival cardiomyocytes inside the engineered heart tissues; and 3) study if delivery of these novel engineered heart tissues to animals with acute or chronic myocardial infarction leads to robust myocardial regeneration and repair.