Role of Progenitor Cells in Cardiovascular Medicine

描述（由申请人提供）：来自我们实验室和其他实验室的数据表明，来自已有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，来自骨髓的循环细胞表现出与EC身份一致的某些特征，能够在生理和病理情况下归巢到新生血管的位置，并有助于新血管的形成。这些细胞被称为内皮祖细胞（EPC）或循环内皮祖细胞（CEP），已被证明参与各种情况下的新生血管形成，包括缺血性组织肿瘤和视网膜。EPCs参与新血管形成的可能性可以调节为治疗益处，最近在循环EPCs移植治疗下肢和心肌缺血性疾病的试点临床试验中进一步提出。然而，尽管有这些令人鼓舞的数据，关于骨髓来源细胞在组织修复和维持中的作用仍有很多未知。大量文献揭示了利用骨髓源性祖细胞的治疗潜力，然而，在某些研究中，骨髓源性细胞参与新血管形成的程度高达30%或更多，而在其他研究中则接近于零。因此，内皮祖细胞促进缺血组织恢复的机制及其治疗潜力仍未完全确定。我们的初步数据显示，骨髓源性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骨髓内皮祖细胞的动员而增强。最后，我们的初步研究结果通过揭示EPCs缺乏或缺陷导致心脏预后不良的情况，为EPCs改善缺血心肌解剖和生理结果的潜在机制提供了重要线索。因此，在本提案中，我们将采用一系列体内和体外模型系统来确定EPCs在心肌缺血恢复中的作用，目标是开发未来利用这些细胞的治疗策略。

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.