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潜力。由于其可塑性，BMSC 具有多谱系潜力，可以克服谱系限制形成包括心肌在内的非造血组织。有确凿的证据表明单核细胞响应组织缺血而从骨髓巢迁移并成为血源性的。这些细胞表现出对缺血心肌的趋向性，在那里它们经历环境依赖性转化并发育成有功能的心肌细胞。我们的长期目标是利用 BMSC 作为治疗药物再生梗塞心肌并修复受损心脏功能的方式。拟议的研究解决了与体外和体内融合相关的一些基本问题缺血性动员的 BMSC 形成心肌细胞的转分化潜力。我们假设缺血性应激的心肌提供了强烈的触发因素来启动特定子细胞的动员 BMSC 群体进入外周循环。血源性细胞追踪受伤者心肌采用心脏表型并改善心脏功能。 BMSC 的表征致力于心脏谱系将有助于理解 BMSC 动员的基本机制以及体外和体内条件下的分化。拟议的三个主要假设项目包括：1) 缺血应激动员特定群体的BMSC细胞进入外周血循环：2) 动员的 BMSC 经历环境依赖性分化为心肌细胞和内皮细胞促进心肌生成和血管生成：3）动员的BMSC保护肌细胞通过分泌特定因子来对抗缺血。实验设计涉及使用来自表达增强型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体外研究BMSC的生物学。它们具有分化成心脏表型的潜力使用心肌梗塞小鼠心脏模型对心脏微环境进行检查。的效果缺血会影响 BMSC 在外周循环中的动员，最终它们在缺血区域的植入将被研究。 BMSC在缺血环境中存活并保护心肌细胞的机制通过检查分子介质来进行研究，例如生长因子、细胞因子、旁分泌因子、由BMSC分泌。广泛的多学科方法，涵盖多种技术，包括组织化学、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具体目标。对正在进行的工作有一个完整的了解干细胞介导的再生的分子过程对于细胞衍生疗法的成功至关重要。