Muscle Stem Cell-based therapies for Cardiomyopathy

基于肌肉干细胞的心肌病疗法

• 批准号: 7663826
• 负责人: Johnny Huard
• 金额: $ 18.43万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7663826
• 关键词: Adenovirus Vector; Adult; Adverse effects; Affect; Angiogenic Factor; Animals; Appendix; Area; Autologous; Behavior; Biological; Biological Assay; Biological Process; Biology; Blood; Blood Vessels; Bone Marrow; Bone Regeneration; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cardiomyoplasty; Cardiovascular Diseases; Cardiovascular system; Cell Differentiation process; Cell Proliferation; Cell Survival; Cell Therapy; Cell Transplantation; Cells; Characteristics; Cicatrix; Collaborations; Condition; Congestive Heart Failure; Coupling; DNA; Data; Dermal; Development; Disease; Duchenne muscular dystrophy; Dystrophin; Embryo; Endothelial Cells; Engineered Gene; Engraftment; Ensure; Environment; Experimental Animal Model; Family suidae; Fibroblasts; Fibrosis; Fostering; Future; Genes; Genetic; Goals; Green Fluorescent Proteins; Harvest; Healed; Heart; Heart Atrium; Heart Diseases; Hematopoietic stem cells; Human; Immune; Implant; In Vitro; Injection of therapeutic agent; Injury; Karyotype; Kidney; LacZ Genes; Letters; Liver; Long-Term Effects; Luciferases; Lung; Mediating; Modeling; Multipotent Stem Cells; Mus; Muscle; Muscle Cells; Muscle Development; Muscle Fibers; Muscle satellite cell; Muscular Dystrophies; Myoblasts; Myocardial; Myocardium; Myofibroblast; Myopathy; Natural regeneration; Neonatal; Numbers; PTPRC gene; Patients; Performance; Phenotype; Play; Population; Procedures; Process; Production; Proliferating; Proteoglycan; Rate; Recovery; Regenerative Medicine; Relative (related person); Reporter Genes; Reporting; Research; Research Personnel; Retroviral Vector; Retroviridae; Rodent; Role; Route; Serum; Site; Skeletal Muscle; Skeletal Myoblasts; Skeletal system; Smooth Muscle Myocytes; Sorting - Cell Movement; Source; Staging; Stem cell transplant; Stem cells; Structure; Survival Rate; Switch Genes; System; Techniques; Technology; Therapeutic; Time; Tissue Engineering; Tissues; Transgenic Mice; Transplantation; Troponin I; Vascular Endothelial Growth Factors; angiogenesis; base; blood pump; cell dedifferentiation; cell type; decorin; design; dosage; embryonic stem cell; fetal; gene therapy; healing; hypertensive heart disease; implantation; improved; in vivo; inhibitor/antagonist; injured; loss of function; mdx mouse; muscle regeneration; muscle transplantation; novel; precursor cell; prevent; promoter; receptor; relating to nervous system; repaired; research study; response to injury; satellite cell; self-renewal; stem cell therapy; success; therapeutic gene; tumor; vector

Cardiomyopathy is a serious heart disease that often leads to congestive heart failure, a condition in which the heart muscle can no longer effectively pump blood. Patients that suffer from various muscle diseases, including Duchenne muscular dystrophy (DMD), develop progressive cardiomyopathy. Cellular cardiomyoplasty (CCM), a procedure that involves the transplantation of exogenous cells into damaged myocardium, has been proposed as a possible therapy to regenerate diseased myocardium and deliver therapeutic genes. Although a wide variety of cell types has been used for CCM, various limitations (including ethical, biological, or technical challenges) have impeded their suitability for use in human patients. We recently have used the modified preplate technique to isolate a novel population of musclederived stem cells (MDSCs) that display improved transplantation capacity in skeletal muscle when compared to satellite cells. The MDSCs' ability to proliferate in vivo for an extended period of time-- combined with their strong capacity for serf-renewal, multipotent differentiation, and immune-t_rivileged behavior--reveals, at least in part, a basis for the benefits associated with their use in cell transplantation in skeletal muscle. The proposed project will investigate the use of MDSCs as a novel cell source for cardiac cell transplantation in a cardiomyopathic murine model of muscular dystrophy. We already have observed that MDSCs delivered by intra-cardiac injection display good cell survival and can deliver dystrophin within the dystrophic myocardium. In this project we will investigate whether MDSCs implanted in the hearts of dystrophic mdx mice display an improved transplantation capacity when compared to conventional satellite cell implantation (Aim #1). We then will explore the relative contribution of the MDSCs' capacity for tong-term proliferation and self-renewal (Aim #2) to the increased regenerative capacity of these cells after transplantation in heart muscle. Finally, we will determine the degree to which development of approaches to prevent fibrosis (Aim #3) and improve angiogenesis (Aim #4) would further enhance the regenerative capacity of muscle-derived cells in the heart. This project will increase our understanding of the basic biology of myogenic cell populations that display stem cell characteristics. This information may, in tum, unveil new techniques to improve heart regeneration and repair via the transplantation of muscle-derived stem cells.

心肌病是一种严重的心脏病，通常会导致充血性心力衰竭，这种情况 心肌无法再有效地泵血。患有各种肌肉疾病的患者， 包括杜氏肌营养不良症 (DMD)，发展为进行性心肌病。蜂窝网络 心肌成形术 (CCM)，一种将外源细胞移植到受损部位的手术 心肌，已被提议作为一种可能的疗法来再生患病的心肌并传递 治疗基因。尽管 CCM 已使用多种细胞类型，但仍存在各种限制 （包括伦理、生物或技术挑战）阻碍了它们在人类中的适用性 患者。我们最近使用改良的预板技术来分离出一个新的肌肉来源群体 干细胞（MDSC）在骨骼肌中表现出改善的移植能力 与卫星细胞相比。 MDSC 在体内长时间增殖的能力—— 结合它们强大的自我更新、多能分化和免疫能力 行为——至少部分地揭示了与它们在细胞移植中的使用相关的益处的基础 骨骼肌。拟议的项目将研究使用 MDSC 作为心脏疾病的新型细胞来源 肌营养不良症心肌病小鼠模型的细胞移植。我们已经观察到 通过心脏内注射递送的 MDSC 显示出良好的细胞存活率，并且可以在心脏内递送肌营养不良蛋白 营养不良的心肌。在这个项目中，我们将研究 MDSC 是否植入心脏 与传统卫星相比，营养不良的 mdx 小鼠表现出更高的移植能力 细胞植入（目标#1）。然后我们将探讨 MDSC 的长期能力的相对贡献 增殖和自我更新（目标＃2）以增加这些细胞的再生能力 心肌移植。最后，我们将确定方法的开发程度 预防纤维化（目标#3）和改善血管生成（目标#4）将进一步增强再生能力 心脏中肌肉来源的细胞的能力。这个项目将增加我们对基础生物学的理解 显示干细胞特征的生肌细胞群。这些信息可能会反过来揭示新的 通过移植肌肉干细胞来改善心脏再生和修复的技术。