Strategies to Enhance Engineered Heart Tissue Based Myocardial Repair

增强基于工程心脏组织的心肌修复的策略

• 批准号: 10581419
• 负责人: Jingwei Xie
• 金额: $ 76.22万
• 依托单位: MAYO CLINIC ARIZONA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10581419
• 关键词: 3-Dimensional; Acute; Acute myocardial infarction; Address; Adult; Animal Model; Animals; Area; Birth; Cardiac; Cardiac Myocytes; Catheters; Cause of Death; Cell Cycle; Cell Proliferation; Cell Survival; Cell Therapy; Cells; Chronic; Cicatrix; Clinical Research; Clinical Trials; Coronary; Data; Diameter; Effectiveness; Engineering; Engraftment; Exhibits; FGF1 gene; Family suidae; Future; Gelatin; Glass; Goals; Heart; Heart failure; Human; Implant; In Vitro; Infarction; Injectable; Injections; Injury; Intervention; Mediating; Modeling; Mus; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardium; Myosin Heavy Chains; Nanofiber Scaffold; Natural regeneration; Nude Rats; Operative Surgical Procedures; Patients; Perfusion; Procedures; Proliferating; Protocols documentation; Rattus; Safety; Shapes; Stem cell transplant; Systolic heart failure; Techniques; Technology; Therapeutic; Thoracic Surgical Procedures; Thoracoscopy; Tissue Engineering; Tissue Transplantation; Tissue constructs; Tissues; Transgenes; Transplantation; Tube; Vascularization; Ventricular Cardiac alpha-Myosin; Virus; cardiac magnetic resonance imaging; cardiac regeneration; cardiac tissue engineering; clinical application; clinically significant; coronary artery occlusion; follow-up; functional restoration; heart dimension/size; heart function; high risk; human embryonic stem cell transplantation; improved; induced pluripotent stem cell; induced pluripotent stem cell derived cardiomyocytes; injured; ischemic injury; minimally invasive; mortality risk; nanomaterials; nanoparticle; novel; novel strategies; overexpression; pre-clinical; preclinical study; promoter; repaired; safety engineering; tumorigenesis; vasculogenesis

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.

项目概要 缺血性心脏病，如不稳定冠心病心绞痛或心肌梗塞，常导致心脏收缩 由于收缩性心肌细胞丧失而导致衰竭。工程心脏组织介导的干细胞移植 细胞衍生的心肌细胞有望再生心肌并改善心脏功能 临床前动物模型中的心肌梗死后。尽管取得了这些令人鼓舞的结果，但一些关键的 障碍限制了基于工程心脏组织的治疗的临床应用。例如，灌注不良 在梗塞区域会损害移植心肌细胞的存活。此外，程序 工程心脏组织的移植通常需要开胸手术，这是一个重大挑战 对于患有严重心力衰竭的患者。我们之前的研究数据表明，促进细胞周期和 人类诱导多能干细胞 (hiPSC-CM) 的增殖构成了增强 移植和恢复缺血性心脏病的功能。我们还生成了一种新型纳米颗粒 通过增加缺血心脏中的血管生成来实现心肌保护。此外，我们 使用 GelMA 涂层的纳米纤维支架建立了可注射且形状可恢复的组织。在这个项目中， 我们的目标是开发新方法，通过整合增强植入 hiPSC-CM 的植入 纳米材料、细胞和组织工程技术。具体来说，我们将1）开发一种新颖的工程 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 这些工程心脏组织和梗塞心脏中的血运重建； 2）利用我们的优势 最近制定了诱导工程心脏内存活心肌细胞增殖的方案 纸巾； 3) 研究是否将这些新型工程心脏组织递送给患有急性或慢性疾病的动物 心肌梗塞导致心肌强大的再生和修复。