Macrophage-derived MMP-8 determines smooth muscle cell differentiation from adventitia stem/progenitor cells and promotes neointima hyperplasia
Macrophage-derived MMP-8 determines smooth muscle cell differentiation from adventitia stem/progenitor cells and promotes neointima hyperplasia
复制标题
巨噬细胞衍生的 MMP-8 决定平滑肌细胞与外膜干/祖细胞的分化并促进新内膜增生
DOI：
10.1093/cvr/cvz044
复制
发表时间：
2020
影响因子：
10.8
通讯作者：
Li Zhang
中科院分区：
文献类型：
--
作者：
Feng Yang;Qishan Chen;Mei Yang;Eithne Margaret Maguire;Xiaotian Yu;Shiping He;Rui Xiao;Claire S. Wang;Weiwei An;Wei Wu;YiJiang Zhou;Qingzhong Xiao;Li Zhang
血管外膜干/祖细胞（AdSPCs）在损伤后迁移到动脉内膜，向平滑肌细胞（SMCs）分化，参与新生内膜增生。我们以前已经确定基质金属蛋白酶-8（MMP-8）作为动脉粥样硬化形成的关键球员。在这项研究中，我们的目的是探讨巨噬细胞衍生的MMP 8在AdSPC分化和损伤诱导的动脉remodeling.Methods和resultsWe的功能作用，我们首先观察到一个重要的作用，MMP 8在SMC分化胚胎干细胞，但这种效果是没有看到在AdSPC。相反，通过巨噬细胞/AdSPC共培养和巨噬细胞条件培养基研究，我们已经证明，从巨噬细胞分泌的MMP 8蛋白促进SMC分化的AdSPC。从机制上讲，我们发现巨噬细胞来源的MMP 8通过调节转化生长因子-β活性和含解整合素和金属蛋白酶结构域的蛋白10（ADAM 10）/Notch 1信号传导促进SMC从AdSPC分化。我们进一步证明了SMC基因启动子中CBF 1、无毛抑制因子和Lag-1（CSL）的结合位点负责Notch 1介导的SMC分化。最后，我们表明，巨噬细胞衍生的MMP 8增加损伤诱导的新生内膜SMC增生激活ADAM 10/Notch 1 signaling.ConclusionsWe已确定巨噬细胞衍生的MMP 8作为调节剂在SMC分化的AdSPC和新生内膜SMC增生在响应损伤。我们的数据提供了新的见解MMP 8在AdSPC分化的作用和血管造影再狭窄的背景下新生内膜形成的发病机制，因此可能有助于开发新的治疗药物，用于预防这种疾病。
AimsEmerging 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 resultsWe 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 forCBF1,Suppressor of Hairless, andLag-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.ConclusionsWe 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.