Role of Progenitor Cells in Cardiovascular Medicine

祖细胞在心血管医学中的作用

• 批准号: 7035583
• 负责人: DOUGLAS W LOSORDO
• 金额: $ 42.5万
• 依托单位: STEWARD ST. ELIZABETH'S MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-01 至 2007-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7035583
• 关键词: angiogenesis; biotechnology; bone marrow transplantation; cardiovascular disorder therapy; cell migration; chemokine receptor; combination therapy; cytoprotection; diabetes mellitus; gene therapy; genetically modified animals; human tissue; ischemic preconditioning; laboratory mouse; myocardial infarction; myocardial ischemia /hypoxia; nitric oxide synthase; regeneration; sonic hedgehog gene /protein; stem cell transplantation; vascular endothelial growth factors; vascular endothelium

DESCRIPTION (provided by applicant): Data from our laboratory and others indicates that endothelial cells (EC) from pre-existing vascular structures might not constitute the sole participants in new vessel formation. These studies have revealed that circulating cells, derived from the bone marrow and exhibiting certain features consistent with EC identity, are capable of homing to sites of neovascularization and contributing to the formation of new vessels in physiologic and pathologic circumstances. These cells, referred to as endothelial progenitors (EPC) or circulating endothelial progenitors (CEP) have been shown to participate in neovascularization in a variety of settings including ischemic tissue tumors, and the retina. The possibility that the participation of EPCs in neovascularization could be modulated to therapeutic benefit has recently been further suggested in pilot clinical trials of circulating EPC transplantation for ischemic diseases of the lower extremity and myocardium. Despite these encouraging data, however, a great deal remains unknown regarding the role of bone marrow derived cells in tissue repair and maintenance. Extensive literature reveals therapeutic potential for exploiting bone marrow derived progenitors, however the reported extent of participation of bone marrow derived cells in neovessel formation has been reported to range as high as 30 or more percent in certain studies, to close to zero in others. The mechanisms by which EPCs contribute to recovery of ischemic tissue, therefore, remain incompletely defined as does their therapeutic potential. Our preliminary data reveal that modulation of bone marrow derived progenitors is associated with improved physiologic outcome in acute and chronic myocardial ischemia. Moreover, these data also reveal that the results of gene therapy mediated therapeutic angiogenesis can be enhanced by bone marrow mobilization of EPCs. Finally, our preliminary findings provide important clues regarding potential mechanisms by which EPCs improve anatomic and physiologic outcome in ischemic myocardium, by revealing situations in which EPCs are deficient or defective, and result in poor cardiac outcome. Accordingly, in this proposal we will employ a series of in vivo and in vitro model systems to define the role of EPCs in recovery from myocardial ischemia with a goal of developing future therapeutic strategies exploiting these cells.

描述（由申请人提供）：我们实验室和其他的数据表明，预先存在的血管结构的内皮细胞（EC）可能不构成新血管形成的唯一参与者。这些研究表明，源自骨髓并表现出与EC身份一致的某些特征的循环细胞能够将其归为新血管形成部位，并有助于在生理和病理状况下形成新血管。这些细胞被称为内皮祖细胞（EPC）或循环内皮祖细胞（CEP），已显示在包括缺血性组织肿瘤和视网膜在内的各种环境中参与新血管化。最近，在下肢和心肌的循环EPC移植循环EPC移植的试验临床试验中进一步提出了EPC参与新血管化的可能性。尽管这些令人鼓舞的数据，但是对于骨髓衍生的细胞在组织修复和维持中的作用方面，仍然未知。广泛的文献揭示了利用骨髓衍生的祖细胞的治疗潜力，但是据报道，在某些研究中，骨髓衍生细胞的参与程度高达30％以上，即接近其他研究。因此，EPC有助于恢复缺血组织的机制仍然没有完全定义，因为其治疗潜力也是如此。我们的初步数据表明，骨髓衍生的祖细胞的调节与急性和慢性心肌缺血的生理结果改善有关。此外，这些数据还表明，基因治疗介导的治疗性血管生成的结果可以通过EPC的骨髓动员来增强。最后，我们的初步发现通过揭示EPC不足或有缺陷并导致心脏不良结果的情况，提供了有关EPC在缺血性心肌中改善解剖学和生理结果的潜在机制的重要线索。因此，在此提案中，我们将采用一系列体内和体外模型系统来定义EPC在从心肌缺血中恢复中的作用，目的是开发利用这些细胞的未来治疗策略。