Mobilized Stem Cells in Cardiomyogenesis & Angiogenesis

心肌发生中的动员干细胞

基本信息

批准号：
7753616
负责人：
MEIFENG XU
金额：
$ 37.26万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-12-01 至 2011-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7753616
关键词：
1-Phosphatidylinositol 3-Kinase ALCAM gene Abbreviations Acetates Activated-Leukocyte Cell Adhesion Molecule Acute myocardial infarction Address Adopted Anterior Descending Coronary Artery Antigens Apoptosis Area Artificial Heart Biology Blood Blood Circulation Blood Vessels Blood capillaries Bone Marrow Bone Marrow Cells Bone Marrow Stem Cell Cardiac Cardiac Myocytes Cardiomyopathies Cardiovascular system Cell Therapy Cell Transplantation Cell model Cells Cessation of life Cloning Coculture Techniques Commit Confocal Microscopy Country Cultured Cells Data Dimensions EFRAC Endothelial Cells Engineering Engraftment Environment Experimental Designs Fibroblast Growth Factor 2 Fluorescence Future Galactosidase Goals Granulocyte Colony-Stimulating Factor Growth Factor Heart Heart failure Hepatocyte Growth Factor Histocytochemistry Home environment In Vitro Infarction Injury Intervention Ischemia LacZ Genes Lactate Dehydrogenase Left Macrophage Colony-Stimulating Factor Mediating Mediator of activation protein Mesenchymal Stem Cells Modality Modeling Molecular Molecular Biology Mononuclear Mus Muscle Cells Myocardial Myocardial Infarction Myocardial Ischemia Myocardium Natural regeneration Nature Pathology Pathway interactions Performance Peripheral Phenotype Phosphotransferases Play Population Prevention Process Propidium Diiodide Proteins Proto-Oncogene Proteins c-akt Regenerative Medicine Reporter Genes Research Research Personnel Role Signal Pathway Smooth Muscle Myocytes Source Stem Cell Factor Stem cells Stress Stromal Cell-Derived Factor 1 Stromal Cells Structure Survival Rate Techniques Testing Therapeutic Tissues Transgenic Mice Transplantation Tropism VWF gene Vascular Endothelial Growth Factor Receptor-2 Vascular Endothelial Growth Factors Ventricular acetyl-LDL angiogenesis base capillary cytokine enhanced green fluorescent protein fluorescence activated cell sorter device heart function hematopoietic tissue immunocytochemistry improved in vivo inhibitor/antagonist injured interdisciplinary approach laser capture microdissection myocyte-specific enhancer-binding factor 2 paracrine phorbol-12-myristate programs receptor reconstitution repaired response success transcription factor transdifferentiation von Willebrand Factor

项目摘要

Bone marrow stromal cells (BMSC) have a great potential in the treatment of myocardial disorders. Due to their malleable nature, BMSC possess multi-lineage potential and can overcome lineage restrictions to form non-hematopoietic tissues including myocardium. There is unflinching evidence that mononuclear cells emigrate from their bone marrow niches in response to tissue ischemia and become blood borne. These cells show tropism for the ischemic myocardium where they undergo milieu dependent transformation and develop into functioning cardiomyocytes. Our long term goal is to exploit BMSC as a therapeutic modality to regenerate the infarcted myocardium and revamp the injured heart function. The proposed study addresses some fundamental issues pertaining to both in vitro as well as in vivo fusion and transdifferentiation potential of ischemically mobilized BMSC to form cardiac myocytes. We postulate that ischemically stressed myocardium provides a strong trigger to initiate mobilization of specific sub- populations of BMSC into peripheral circulation. The blood-borne cells home onto the injured myocardium to adopt cardiac phenotvpes and improve cardiac function. Characterization of BMSC committed to cardiac lineage will help to understand the basic mechanisms underlying BMSC mobilization and differentiation both in vitro and in vivo conditions. Three main hypotheses fundamental to the proposed project include: 1) ischemic stress mobilizes specific population of BMSC cells into peripheral circulation: 2) Mobilized BMSC undergo milieu dependent differentiation into cardiomvocvtes and endothelial cells to promote cardiomyogenesis and angiogenesis: 3) Mobilized BMSC protect myocvtes against ischemia by secreting specific factors. The experimental design involves the use of BMSC from transgenic mice expressing enhanced green fluorescent protein. Co-culture cell model will be used to study the biology of BMSC in vitro. Their potential to differentiate into cardiac phenotypes in a cardiac microenvironment using murine heart model of myocardial infarction will be examined. The effect of ischemia on BMSC mobilization in peripheral circulation and finally their engraftment in the ischemic area will be studied. The mechanism by which BMSC survive in the ischemic environment and protect myocytes will be investigated by examining the molecular mediators, such as growth factors, cytokines, paracrine factors, secreted by the BMSC. A broad multidisciplinary approach that will encompass diverse techniques including histochemistry, immunocytochemistry, pathology, flow cytometric analysis, confocal microscopy and molecular biology will be used to investigate the specific aims. A complete understanding of the ongoing molecular processes in stem cell mediated regeneration is central to the success of cell derived-therapy.

骨髓基质细胞（BMSC）在治疗心肌疾病方面具有巨大的潜力。由于其可延展性，BMSC具有多条款的潜力，并且可以克服血统限制形成包括心肌在内的非杂造组织。有明确的证据表明单核细胞从其骨髓壁ni中移民，以响应组织缺血并成为血液。这些细胞显示出缺血性心肌的朝向主义，在那里它们进行环境依赖性转化并发展为功能性的心肌细胞。我们的长期目标是利用BMSC作为治疗将梗塞心肌再生并改变受伤的心脏功能的方式。拟议的研究解决了与体外以及体内融合有关的一些基本问题跨化的跨化潜力动员BMSC形成心肌细胞。我们假设在不良压力的心肌上，为引发特定亚的动员提供了强烈的触发因素 BMSC的种群进入外围循环。血源细胞回家到受伤的心肌采用心脏表现象并改善心脏功能。 BMSC的表征致力于心脏血统将有助于了解BMSC动员基本的基本机制以及体外和体内条件的分化。提议的三个主要假设项目包括：1）缺血应力动员BMSC细胞的特定群体循环：2）动员BMSC经历了环境依赖分化为心脏杂志和内皮细胞促进心肌生成和血管生成：3）动员BMSC保护通过分泌特定因素来抵抗缺血的肌肉。实验设计涉及使用来自表达增强绿色荧光蛋白的转基因小鼠的BMSC。共培养细胞模型将是用于在体外研究BMSC的生物学。它们在A中区分为心脏表型的潜力将检查使用心肌梗死的鼠心脏模型的心脏微环境。效果 BMSC动员外周循环中的缺血及其在缺血区域的植入被研究。 BMSC在缺血环境中生存并保护心肌细胞的机制将可以通过检查分子介质，例如生长因子，细胞因子，旁分泌因子，由BMSC分泌。一种广泛的多学科方法，它将包括多种技术组织化学，免疫细胞化学，病理学，流式细胞术分析，共聚焦显微镜和分子生物学将用于研究特定目的。完全了解正在进行的干细胞介导的再生中的分子过程对于细胞衍生疗法的成功至关重要。