Academic Department of Surgery, Cardiovascular Division, King's College London, Biomedical Research Centre at Guy's & St Thomas' NHS Foundation Trust and King's College London, UK.
EMBO Mol Med. 2013 Jun;5(6):858-69. doi: 10.1002/emmm.201302752. Epub 2013 May 7.
A third of patients with critical limb ischemia (CLI) will eventually require limb amputation. Therapeutic neovascularization using unselected mononuclear cells to salvage ischemic limbs has produced modest results. The TIE2-expressing monocytes/macrophages (TEMs) are a myeloid cell subset known to be highly angiogenic in tumours. This study aimed to examine the kinetics of TEMs in patients with CLI and whether these cells promote neovascularization of the ischemic limb. Here we show that there are 10-fold more circulating TEMs in CLI patients, and removal of ischemia reduces their numbers to normal levels. TEM numbers in ischemic muscle are two-fold greater than normoxic muscle from the same patient. TEMs from patients with CLI display greater proangiogenic activity than TIE2-negative monocytes in vitro. Using a mouse model of hindlimb ischemia, lentiviral-based Tie2 knockdown in TEMs impaired recovery from ischemia, whereas delivery of mouse macrophages overexpressing TIE2, or human TEMs isolated from CLI patients, rescued limb ischemia. These data suggest that enhancing TEM recruitment to the ischemic muscle may have the potential to improve limb neovascularization in CLI patients.
三分之一的严重肢体缺血 (CLI) 患者最终将需要截肢。使用未经选择的单核细胞进行治疗性新生血管化以挽救缺血肢体的效果并不理想。表达 TIE2 的单核细胞/巨噬细胞 (TEM) 是一种已知在肿瘤中具有高度血管生成能力的髓样细胞亚群。本研究旨在检查 CLI 患者中 TEM 的动力学特征，以及这些细胞是否促进缺血肢体的新生血管化。本研究显示，CLI 患者的循环 TEM 数量增加了 10 倍，而缺血的消除将其数量降低至正常水平。与来自同一患者的正常氧合肌肉相比，缺血肌肉中的 TEM 数量增加了两倍。与 TIE2 阴性单核细胞相比，CLI 患者的 TEM 显示出更强的促血管生成活性。在小鼠后肢缺血模型中，TEM 中的基于慢病毒的 Tie2 敲低会损害缺血的恢复，而过表达 TIE2 的小鼠巨噬细胞或从 CLI 患者中分离出的人 TEM 的递呈则可以挽救肢体缺血。这些数据表明，增强 TEM 向缺血肌肉的募集可能有潜力改善 CLI 患者的肢体新生血管化。
