Cell Therapy in Hypertrophied and Remodeled Left Ventricle

左心室肥大和重塑的细胞疗法

• 批准号: 9391517
• 负责人: Jianyi Zhang
• 金额: $ 64.65万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-10 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9391517
• 关键词: ATP Hydrolysis; Alabama; Allografting; Animals; Antigens; Arrhythmia; Bioenergetics; Blood Vessels; Cardiac; Cardiac Myocytes; Cell Differentiation process; Cell Line; Cell Therapy; Cell Transplantation; Cell Transplants; Cells; Chest; Cicatrix; Clinic; Clinical; Connexin 43; Connexins; Creatine Kinase; Diagnostic; Donor person; Early Diagnosis; Electrocardiogram; Electrophysiology (science); Endothelial Cells; Engraftment; Family suidae; Functional disorder; Future; Genes; Graft Survival; HLA Antigens; Heart; Heart Atrium; Heart failure; Histocompatibility Antigens Class I; Human; Human Engineering; Hypertrophy; Immune system; Implant; In Vitro; Infarction; Injection of therapeutic agent; Knock-out; Lead; Left Ventricular Remodeling; Magnetic Resonance Spectroscopy; Measures; Mechanics; Mediating; Methods; Mitochondria; Modality; Modeling; Mole the mammal; Monitor; Muscle; Muscle Cells; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardial tissue; Myocardium; NMR Spectroscopy; Noise; Optics; Patients; Performance; Perfusion; Phosphocreatine; Preparation; Proteins; Reporting; Risk; Safety; Signal Transduction; Smooth Muscle Myocytes; Spectrum Analysis; Stress; Stretching; Surface; System; T-Lymphocyte; Techniques; Technology; Testing; Therapeutic; Thick; Tissues; Transplantation; Universities; Ventricular; allograft rejection; base; design; electrical property; experimental study; functional outcomes; immunosuppressed; improved; in vivo; induced pluripotent stem cell; inorganic phosphate; insight; mechanical properties; nonhuman primate; novel; overexpression; prevent; protein expression; stem cell therapy; technology validation

Cell Therapy in Hypertrophied and Remodeled Left Ventricle ABSTRACT The recent report of increased arrhythmic potential in hearts of non-human primates that received cell therapy causes serious concerns in field of cardiac stem cell therapy. Although the beneficial effects of human induced pluripotent stem cell (hiPSC) cellular therapy in hearts with post myocardial infarction (MI) have been recently reported in large animal studies, there could be additional benefits in applying a highly functional prefabricated cardiac muscle tissue equivalent over the MI surface. The specific aims (SA) are: SA1. To fabricate the larger and thicker human cardiac muscle patch (hCMP) using the hiPSC - cardiomyocytes (CM), - smooth muscle cells (SMC) and – endothelial cells (EC). We will fabricate a new type of larger and thicker hCMP and characterize its vascular, electrical, and mechanical properties in vitro. To increase the engraftment rate, we will generate hiPSC lines by engineering the hiPSC, in which human HLA Class I and/or Class II protein expression have been knocked out (HLA-KO -hCMP) by the gene editing technology. To reduce the arrhythmogenic potential, we will generate hiPSC lines by engineering the hiPSC to overexpress the gap junction protein: Cx43 (Cx43-hCMP). SA2. Using an immuno-suppressed porcine model of post-infarction LV remodeling, we will examine whether the transplantation of a prefabricated hCMP will result in better functional outcomes in reductions in LV scar bulging and wall stress, and improvements in myocardial bioenergetics and contractile function as compared to standard cell injection. We will compare the electrical stability of hearts with or without hCMP transplantation by continuously monitoring ECG for 8 weeks in vivo, and by conducting ex vivo dual optical mapping studies of electrical propagation. We will develop the completely non-invasive NMR technology that will provide unprecedented levels of sensitivity and signal-to-noise ratio (SNR) for P-31 NMR spectroscopy measuring the myocardial ATP hydrolysis rate with a precision of micro moles/s per gram of myocardium in a large bore magnet, which can be applied clinically. The findings of the studies will advance our understanding of the mechanisms of functional benefits of cell therapy in hearts with post-infarction LV remodeling, which can lead to better diagnostic and therapeutic modalities for CHF patients.

细胞治疗左心室肥大和重塑 摘要 最近有报道称，接受细胞治疗的非人类灵长类动物心脏的心肌细胞潜能增加， 引起了心脏干细胞治疗领域的严重关注。虽然人类诱导的有益效果 心肌梗死后心脏的多能干细胞（hiPSC）细胞治疗最近已被 在大型动物研究中报告，在应用高功能预制的 心肌梗死表面上的心肌组织等效物。具体目标（SA）为：SA 1。为了制造更大的 使用hiPSC -心肌细胞（CM）、-平滑肌 细胞（SMC）和内皮细胞（EC）。我们将制造一种更大更厚的新型hCMP， 在体外表征其血管、电和机械特性。为了提高移植率，我们 将通过工程化hiPSC产生hiPSC系，其中人HLA I类和/或II类蛋白 通过基因编辑技术敲除（HLA-KO -hCMP）。减少 我们将通过工程改造hiPSC以过表达差距来产生hiPSC系 连接蛋白：Cx43（Cx43-hCMP）。SA 2.使用免疫抑制的猪梗死后左室模型 重建，我们将检查是否移植预制hCMP将导致更好的功能， 减少LV瘢痕膨出和室壁应力，改善心肌生物能量学， 与标准细胞注射相比的收缩功能。我们会比较心脏的电稳定性 通过在体内连续监测ECG 8周，并通过在有或没有hCMP移植的情况下进行 电传播的离体双光学映射研究。我们将开发完全非侵入性的 NMR技术将为P-31提供前所未有的灵敏度和信噪比（SNR） 核磁共振波谱测量心肌ATP水解速率，精度为微摩尔/秒/克 心肌在大口径磁铁，这可以应用于临床。这些研究的结果将推动 我们对心肌梗死后左心室细胞治疗功能获益机制的理解 重塑，这可以为CHF患者带来更好的诊断和治疗方式。