AIMS Emerging evidence has suggested that adventitia stem/progenitor cells (AdSPCs) migrate into the intima of arteries in response to injury, where they differentiate towards smooth muscle cells (SMCs) and participate in neointimal hyperplasia. We have previously identified matrix metalloproteinase-8 (MMP8) as a key player in atherogenesis. In this study, we aimed to investigate the functional roles of macrophage-derived MMP8 in AdSPC differentiation and injury-induced arterial remodelling. METHODS AND RESULTS We first observed an important role for MMP8 in SMC differentiation from embryonic stem cells, but this effect was not seen in AdSPCs. Instead, through macrophages/AdSPCs co-culture and macrophage conditional culture medium studies, we have demonstrated that the MMP8 protein secreted from macrophages promotes SMC differentiation from AdSPCs. Mechanistically, we showed that macrophage-derived MMP8 promotes SMC differentiation from AdSPCs through modulating transforming growth factor-β activity and a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10)/Notch1 signalling. We further demonstrated that the binding site for CBF1, Suppressor of Hairless, and Lag-1 (CSL) within SMC gene promoters is responsible for Notch1 mediated SMC differentiation. Finally, we demonstrated that macrophage-derived MMP8 increased injury-induced neointimal SMC hyperplasia by activating ADAM10/Notch1 signalling. CONCLUSIONS We have identified macrophage-derived MMP8 as a regulator in SMC differentiation from AdSPCs and neointimal SMC hyperplasia in response to injury. Our data provide new insights into the roles of MMP8 in AdSPC differentiation and the pathogenesis of neointima formation in the context of angiographic restenosis, and therefore may aid in the development of novel therapeutic agents for the prevention of this disease.

中文翻译：

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巨噬细胞衍生的MMP-8决定了外膜干细胞/祖细胞的平滑肌细胞分化，并促进了新内膜增生。

AIMS越来越多的证据表明，外膜干/祖细胞（AdSPC）响应损伤而迁移到动脉内膜，在此分化为平滑肌细胞（SMC）并参与新内膜增生。我们之前已经确定基质金属蛋白酶8（MMP8）是动脉粥样硬化的关键因素。在这项研究中，我们旨在调查巨噬细胞衍生的MMP8在AdSPC分化和损伤诱导的动脉重塑中的功能。方法和结果我们首先观察到MMP8在SMC从胚胎干细胞分化中的重要作用，但在AdSPC中未发现这种作用。相反，通过巨噬细胞/ AdSPCs共培养和巨噬细胞条件培养基研究，我们已经证明巨噬细胞分泌的MMP8蛋白可促进AdSPC分化为SMC。从机制上讲，我们表明巨噬细胞衍生的MMP8通过调节转化生长因子-β活性以及包含整联蛋白和金属蛋白酶结构域的蛋白10（ADAM10）/ Notch1信号传导，促进了AdSPC的SMC分化。我们进一步证明SMC基因启动子内CBF1，无毛抑制物和Lag-1（CSL）的结合位点负责Notch1介导的SMC分化。最后，我们证明了巨噬细胞衍生的MMP8通过激活ADAM10 / Notch1信号传导增加了损伤诱导的新内膜SMC增生。结论我们已经鉴定出巨噬细胞衍生的MMP8是AdSPCs和新内膜SMC增生对损伤的分化中SMC分化的调节剂。