基质金属蛋白酶-8在调控干细胞向血管平滑肌细胞分化及血管损伤修复中的作用机制研究

Vascular injury and repair play an essential role in all kinds of vascular diseases. Growing evidence suggests that vascular smooth muscle cell (VSMC) differentiation from vascular wall derived stem cells is a critical process during the VSMC proliferative related cardiovascular disease, such as atherosclerosis and postangioplasty restenosis. Recent studies from our group suggest that matrix metalloproteinase 8 (MMP8) may play an important role in promoting stem cell differentiation into VSMCs and neointimal formation after mouse femoral artery wire injury. These finding provides a foundation for the proposal’s central hypothesis: MMP8 play pivotal role in regulating VSMC differentiation from stem cells and is attributable to vascular injury related disease. To test our hypothesis, studies will be conducted addressing four specific aims: 1) to further assess the impact of MMP8 in VSMC differentiation from stem cells and other cellular function including proliferation, migration, contractile capacity and vessel formation; 2) to explore the effect of MMP8 on stem cell migration，differentiation into VSMCs and neointimal formation after vessel injury by using the MMP8 knockout and wildtype mice; 3) to verify whether MMP8-ADAM10-Notch signaling pathways is one of the potential molecular pathways involved in MMP8 regulation of VSMC differentiation; 4) to fully explore the key factors mediating MMP8 effect on VSMC differentiation by using genomics and proteomics analysis. Results of the study would help to better understand the biological mechanisms underlying SMC differentiation and injury-induced neointima formation, and could provide a new strategy for therapeutic intervention in vascular injury related disease.

血管损伤修复是各种血管疾病发生发展的共同基础，近年研究发现干细胞向血管平滑肌细胞（VSMCs）分化在血管损伤中至关重要。我们前期研究发现基质金属蛋白酶8（MMP8）促进干细胞向VSMCs分化，因此我们假设MMP8通过影响该分化过程，在血管损伤中起重要作用。本项目拟1）评估MMP8在干细胞向VSMCs分化中的作用及其对分化来的VSMCs功能的影响；2）采用MMP8基因敲除小鼠制备血管损伤模型，观察MMP8对血管壁干细胞迁移、分化成VSMCs的影响及其在新生内膜形成中的作用；3）验证MMP8对VSMCs分化和功能的影响是否通过MMP8-ADAM10-Notch信号途径来实现；4) 采用基因组和蛋白组学策略系统分析在MMP8缺失状态下,干细胞向VSMCs分化过程中差异基因和蛋白的表达,以全面探讨其分子机制。发现MMP-8关键调控因子及揭示其作用机制，有可能为重大血管损伤性疾病提供新的干预靶点。

血管损伤修复和新生内膜的形成是各种血管损伤性疾病发生发展的共同基础，近年研究发现干细胞向血管平滑肌细胞（VSMCs）分化在血管损伤中具有极其重要的作用。我们前期研究发现基质金属蛋白酶8（MMP8）促进干细胞向VSMCs分化，因此我们假设MMP8通过影响该分化过程，在血管损伤中起重要作用。本项目已完成以下工作：1）确认MMP8在干细胞向VSMCs分化中具有促进作用及其对分化来的VSMCs功能的影响；2）采用MMP8基因敲除小鼠制备血管损伤模型，确认敲除MMP8对血管壁干细胞迁移、分化成VSMCs和新生内膜形成具有抑制作用；3）证实骨髓来源的MMP8对VSMCs分化和功能的影响是通过MMP8-ADAM10-Notch1信号途径来实现.本研究发现MMP-8是干细胞分化为血管平滑肌细胞的关键调控因子及并揭示了其作用机制，有可能为重大血管损伤性疾病提供新的干预靶点。