Qin Gangjian, Ii Masaaki, Silver Marcy, Wecker Andrea, Bord Evelyn, Ma Hong, Gavin Mary, Goukassian David A, Yoon Young-sup, Papayannopoulou Thalia, Asahara Takayuki, Kearney Marianne, Thorne Tina, Curry Cynthia, Eaton Liz, Heyd Lindsay, Dinesh Deepika, Kishore Raj, Zhu Yan, Losordo Douglas W
Cardiovascular Research, Caritas St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, MA 02135.
J Exp Med. 2006 Jan 23;203(1):153-63. doi: 10.1084/jem.20050459. Epub 2006 Jan 9.
The cell surface receptor alpha4 integrin plays a critical role in the homing, engraftment, and maintenance of hematopoietic progenitor cells (HPCs) in the bone marrow (BM). Down-regulation or functional blockade of alpha4 integrin or its ligand vascular cell adhesion molecule-1 mobilizes long-term HPCs. We investigated the role of alpha4 integrin in the mobilization and homing of BM endothelial progenitor cells (EPCs). EPCs with endothelial colony-forming activity in the BM are exclusively alpha4 integrin-expressing cells. In vivo, a single dose of anti-alpha4 integrin antibody resulted in increased circulating EPC counts for 3 d. In hindlimb ischemia and myocardial infarction, systemically administered anti-alpha4 integrin antibody increased recruitment and incorporation of BM EPCs in newly formed vasculature and improved functional blood flow recovery and tissue preservation. Interestingly, BM EPCs that had been preblocked with anti-alpha4 integrin ex vivo or collected from alpha4 integrin-deficient mice incorporated as well as control cells into the neovasculature in ischemic sites, suggesting that alpha4 integrin may be dispensable or play a redundant role in EPC homing to ischemic tissue. These data indicate that functional disruption of alpha4 integrin may represent a potential angiogenic therapy for ischemic disease by increasing the available circulating supply of EPCs.
细胞表面受体α4整合素在造血祖细胞（HPC）归巢、植入以及在骨髓（BM）中的维持过程中发挥关键作用。α4整合素或其配体血管细胞黏附分子-1的下调或功能阻断可动员长期HPC。我们研究了α4整合素在骨髓内皮祖细胞（EPC）动员和归巢中的作用。骨髓中具有内皮集落形成活性的EPC是仅表达α4整合素的细胞。在体内，单剂量抗α4整合素抗体可使循环EPC计数在3天内增加。在下肢缺血和心肌梗死中，全身给予抗α4整合素抗体可增加骨髓EPC在新形成血管中的募集和掺入，并改善功能性血流恢复和组织保存。有趣的是，体外预先用抗α4整合素阻断或从α4整合素缺陷小鼠收集的骨髓EPC与对照细胞一样掺入缺血部位的新生血管中，这表明α4整合素在EPC归巢至缺血组织中可能是可有可无的或发挥冗余作用。这些数据表明，α4整合素的功能破坏可能通过增加循环中可用的EPC供应而成为缺血性疾病的一种潜在血管生成疗法。
