Mobilized Stem Cells in Cardiomyogenesis & Angiogenesis

心肌发生中的动员干细胞

• 批准号: 7021267
• 负责人: MEIFENG XU
• 金额: $ 36.48万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-12-01 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7021267
• 关键词: angiogenesis; bone marrow; cardiac myocytes; cardiogenesis; cardiovascular disorder therapy; cell cell interaction; cell differentiation; cell migration; cell population study; confocal scanning microscopy; cytokine; cytoprotection; genetically modified animals; growth factor; immunocytochemistry; laboratory mouse; mixed tissue /cell culture; myocardial infarction; myocardial ischemia /hypoxia; nonhuman therapy evaluation; regeneration; stem cell transplantation; stromal cells; therapy design /development; transcription factor; vascular endothelium

DESCRIPTION (provided by applicant): 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 phenotypes 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 cardiomyocytes and endothelial cells to promote cardiomyogenesis and angiogenesis: 3) Mobilized BMSC protect myocytes 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.

描述（由申请人提供）：骨髓基质细胞（BMSC）在治疗心肌疾病方面具有很大的潜力。由于其可延展性的性质，BMSC具有多条款的潜力，并且可以克服谱系限制，以形成包括心肌在内的非杂造组织。有明显的证据表明，单核细胞从其骨髓壁ni中移民而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，在那里它们经历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作为治疗方式，以再生梗塞心肌并改善受伤的心脏功能。拟议的研究探讨了与体外以及体内融合以及缺口动员BMSC形成心脏肌细胞的一些基本问题。我们假设在不理压力的心肌上为将特定的BMSC的特定亚群启动到外周循环中提供了强烈的触发因素。血源细胞回家到受伤的心肌中，采用心脏表型并改善心脏功能。致力于心脏血统的BMSC的表征将有助于了解BMSC动员和分化的基本机制，包括体外和体内条件。拟议项目基本的三个主要假设包括：1）缺血性压力将BMSC细胞的特定人群动员到周围循环中：2）动员BMSC经历了环境依赖性的分化，分化为心肌细胞和内皮细胞，以促进心脏正理发生和血管生成：3）动员BMSC保护肌组织肌肉肌细胞。通过分泌特定因素的缺血。实验设计涉及使用表达增强绿色荧光蛋白的转基因小鼠的BMSC。共培养细胞模型将用于研究体外BMSC的生物学。他们将使用心肌梗死的鼠心脏模型在心脏微环境中区分心脏表型的潜力。缺血对周围循环中BMSC动员的影响以及其在缺血区域的植入的影响。 BMSC在缺血环境中生存并保护肌细胞的机制将通过检查BMSC分泌的分子介质，例如生长因子，细胞因子，旁分泌因子，例如生长因子，细胞因子，旁分泌因子。一种广泛的多学科方法，该方法将涵盖各种技术，包括组织化学，免疫细胞化学，病理学，流式细胞仪分析，共聚焦显微镜和分子生物学，以研究具体目标。对干细胞介导的再生中正在进行的分子过程的完全理解对于细胞衍生疗法的成功至关重要。