Role of Progenitor Cells in Cardiovascular Medicine

描述(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，来自骨髓的循环细胞表现出与EC特征一致的某些特征，能够在生理和病理环境中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)，已被证明参与了包括缺血组织、肿瘤和视网膜在内的各种环境中的新生血管形成。最近，循环内皮祖细胞移植治疗肢体和心肌缺血性疾病的先导性临床试验进一步表明，内皮祖细胞参与新生血管形成的可能性可以被调节为治疗效益。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，仍然有很大的未知。大量文献揭示了利用骨髓来源的前体细胞的治疗潜力，然而，据报道，在某些研究中，骨髓来源的细胞参与新生血管形成的程度高达30%或更多，而在另一些研究中，则几乎为零。因此，内皮祖细胞促进缺血组织恢复的机制以及它们的治疗潜力仍未完全确定。我们的初步数据显示，骨髓来源的祖细胞的调节与急性和慢性心肌缺血的生理学结果的改善有关。此外，这些数据还表明，通过骨髓动员内皮祖细胞可以增强基因治疗介导的治疗性血管生成的结果。最后，我们的初步发现通过揭示内皮祖细胞缺陷或缺陷并导致不良心脏结局的情况，提供了关于内皮祖细胞改善缺血心肌解剖和生理结局的潜在机制的重要线索。因此，在这项提案中，我们将使用一系列体内和体外模型系统来确定内皮祖细胞在心肌缺血恢复中的作用，目标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.