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.

肥厚和重塑左心室的细胞治疗 摘要 最近关于接受细胞治疗的非人灵长类动物心脏心律失常电位增加的报道 引起了心脏干细胞治疗领域的严重关注。尽管人类所产生的有益影响 多能干细胞(HiPSC)细胞治疗心肌梗死后心肌梗死(MI)的研究进展 在大型动物研究中报道，应用高功能预制件可能会有额外的好处 心肌梗死表面的心肌组织当量。具体目标(SA)是：SA1。制造更大的 使用HiPSC-心肌细胞(CM)和更厚的人心肌贴片(HCMP)，-平滑肌肉 细胞(SMC)和内皮细胞(EC)。我们将制造一种更大更厚的新型羟基磷灰石和 在体外对其血管、电和机械性能进行表征。为了提高植入率，我们 将通过设计HiPSC来产生HiPSC系，其中人HLAI类和/或II类蛋白 基因编辑技术已经敲除了基因的表达(HLA-KO-hCMP)。以减少 致心律失常的潜力，我们将通过改造HiPSC来过表达GAP来产生HiPSC系 连接蛋白：Cx43(Cx43-hCMP)。SA2.利用免疫抑制的猪心肌梗死后左室缩窄模型 重建，我们将研究移植预制的hCMP是否会带来更好的功能 减少左室瘢痕隆起和室壁应力的结果，以及改善心肌生物能量学和 收缩功能与标准细胞注射相比。我们将比较心脏的电稳定性 在体内连续监测8周的心电图，并通过进行hCMP移植 电传播的体外双光学标测研究。我们将开发完全非侵入性的 核磁共振技术将为P-31提供前所未有的灵敏度和信噪比(SNR) 核磁共振法测定心肌细胞三磷酸腺苷水解率，精密度为微摩尔/S/克 在大口径磁铁中检测心肌组织，可应用于临床。这些研究的结果将会取得进展 我们对细胞疗法对心肌梗死后左心功能有益机制的理解 重塑，这可以为CHF患者带来更好的诊断和治疗方式。