Role of Progenitor Cells in Cardiovascular Medicine

描述（由申请方提供）：来自我们实验室和其他实验室的数据表明，来自预先存在的血管结构的内皮细胞（EC）可能不是新血管形成的唯一参与者。这些研究表明，循环细胞，来自骨髓，并表现出某些功能一致的EC身份，是能够归巢的网站的新血管形成的生理和病理情况下，新的血管的形成。这些细胞被称为内皮祖细胞（EPC）或循环内皮祖细胞（CEP），已被证明参与包括缺血性组织肿瘤和视网膜在内的各种环境中的新血管形成。最近在循环EPC移植治疗下肢和心肌缺血性疾病的临床试验中进一步提出了EPC参与新生血管形成的可能性。尽管有这些令人鼓舞的数据，但是，关于骨髓来源的细胞在组织修复和维护中的作用仍然有很多未知之处。大量文献揭示了利用骨髓来源的祖细胞的治疗潜力，然而，据报道，骨髓来源的细胞参与新血管形成的程度在某些研究中高达30%或更多，在其他研究中接近于零。因此，EPCs促进缺血组织恢复的机制仍不完全确定，其治疗潜力也是如此。我们的初步数据表明，骨髓来源的祖细胞的调制与改善急性和慢性心肌缺血的生理结果。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骨髓动员EPCs来增强。最后，我们的初步研究结果提供了重要的线索，通过揭示EPCs缺乏或缺陷的情况下，EPCs改善缺血心肌的解剖和生理结果的潜在机制，并导致心脏预后不良。因此，在本提案中，我们将采用一系列的体内和体外模型系统，以确定EPCs在心肌缺血恢复中的作用，目的是开发利用这些细胞的未来治疗策略。

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.