Role of Progenitor Cells in Cardiovascular Medicine

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）可能不会 成为新船编队的唯一参与者。这些研究表明，循环细胞，来源于 骨髓并表现出与EC身份一致的某些特征，能够归巢到 在生理和病理情况下，血管新生和促进新血管的形成。这些 称为内皮祖细胞（EPC）或循环内皮祖细胞（CEP）的细胞已经显示出 参与各种环境中的新血管形成，包括缺血性组织肿瘤和视网膜。的可能性 EPCs参与新生血管形成可以被调节以获得治疗益处，这一点最近得到了进一步的证实。 在循环EPC移植治疗下肢缺血性疾病的初步临床试验中提出， 心肌尽管有这些令人鼓舞的数据，然而，关于骨骼的作用， 骨髓来源的细胞在组织修复和维护中的作用。大量的文献揭示了利用 骨髓来源的祖细胞，然而，所报道的骨髓来源的细胞参与neo- 据报道，血管形成在某些研究中高达30%或更高，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， 我们的初步数据显示，骨髓来源的祖细胞的调节， 与改善急性和慢性心肌缺血的生理结果相关。此外，这些数据还 表明骨髓动员可以增强基因治疗介导的治疗性血管生成的结果 的EPC。最后，我们的初步研究结果提供了重要的线索，关于EPCs的潜在机制， 通过揭示EPCs在缺血心肌中的位置，改善缺血心肌的解剖和生理结果， 缺乏或有缺陷，并导致不良的心脏结果。因此，在本提案中，我们将采用一系列 体内和体外模型系统，以确定EPCs在心肌缺血恢复中的作用， 开发利用这些细胞的未来治疗策略。

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 includingischemic 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 unknownregarding 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 neo- vessel 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.