From the Cardiovascular Division, King's College London BHF Centre, London, United Kingdom (M.M.W., A.M., B.W., P.C., C.P., Y.H., Q.X.); and Department of Vascular Surgery, Second Affiliated Hospital, Chongqing Medical University, Chongqing, China (Y.C.).
Arterioscler Thromb Vasc Biol. 2014 Mar;34(3):635-43. doi: 10.1161/ATVBAHA.113.302568. Epub 2014 Jan 23.
Vascular lineage differentiation of stem/progenitor cells can contribute to both tissue repair and exacerbation of vascular diseases such as in vein grafts. The role of macrophages in controlling vascular progenitor differentiation is largely unknown and may play an important role in graft development. This study aims to identify the role of macrophages in vascular stem/progenitor cell differentiation and thereafter elucidate the mechanisms that are involved in the macrophage- mediated process.
We provide in vitro evidence that macrophages can induce endothelial cell (EC) differentiation of the stem/progenitor cells while simultaneously inhibiting their smooth muscle cell differentiation. Mechanistically, both effects were mediated by macrophage-derived tumor necrosis factor-α (TNF-α) via TNF-α receptor 1 and canonical nuclear factor-κB activation. Although the overexpression of p65 enhanced EC (or attenuated smooth muscle cell) differentiation, p65 or TNF-α receptor 1 knockdown using lentiviral short hairpin RNA inhibited EC (or rescued smooth muscle cell) differentiation in response to TNF-α. Furthermore, TNF-α-mediated EC differentiation was driven by direct binding of nuclear factor-κB (p65) to specific VE-cadherin promoter sequences. Subsequent experiments using an ex vivo decellularized vessel scaffold confirmed an increase in the number of ECs and reduction in smooth muscle cell marker expression in the presence of TNF-α. The lack of TNF-α in a knockout mouse model of vein graft decreased endothelialization and significantly increased thrombosis formation.
Our study highlights the role of macrophages in directing vascular stem/progenitor cell lineage commitment through TNF-α-mediated TNF-α receptor 1 and nuclear factor-κB activation that is likely required for endothelial repair in vascular diseases such as vein graft.
干细胞/祖细胞的脉管谱系分化既能促进组织修复，又能加剧静脉移植物等血管疾病的恶化。巨噬细胞在控制血管祖细胞分化中的作用在很大程度上尚不清楚，但可能在移植物发育中发挥重要作用。本研究旨在确定巨噬细胞在血管干细胞/祖细胞分化中的作用，并阐明其介导过程中涉及的机制。
我们提供了体外证据，表明巨噬细胞可以诱导干细胞/祖细胞向内皮细胞（EC）分化，同时抑制其平滑肌细胞分化。从机制上讲，这两种作用都是由巨噬细胞衍生的肿瘤坏死因子-α（TNF-α）通过 TNF-α 受体 1 和经典核因子-κB 激活介导的。虽然 p65 的过表达增强了 EC（或减弱了平滑肌细胞）分化，但使用慢病毒短发夹 RNA 对 p65 或 TNF-α 受体 1 的敲低抑制了 TNF-α 诱导的 EC（或挽救了平滑肌细胞）分化。此外，TNF-α 介导的 EC 分化是由核因子-κB（p65）与特定 VE-钙粘蛋白启动子序列的直接结合驱动的。随后在使用脱细胞化血管支架的离体实验中证实，在存在 TNF-α 的情况下，EC 的数量增加，平滑肌细胞标志物的表达减少。在静脉移植物的 TNF-α 敲除小鼠模型中缺乏 TNF-α 会减少内皮化，并显著增加血栓形成。
我们的研究强调了巨噬细胞通过 TNF-α 介导的 TNF-α 受体 1 和核因子-κB 激活在指导血管干细胞/祖细胞谱系定向中的作用，这可能是血管疾病如静脉移植物中内皮修复所必需的。
