骨髓间充质干细胞心肌保护的新机制：MyD88-HMGB1/STAT3信号介导的旁分泌因子释放

Ischemia reperfusion injury (I/R) is an important complication in patients with acute myocardial infarction (AMI) after coronary artery recanalization, currently there is still a lack of effective prevention and control measures. Paracrine factors (VEGF、FGF&HGF, etc) secreted by bone marrow mesenchymal stem cell (BM-MSC) could alleviate I/R injury and improve AMI patient’s cardiac function, but the exact release regulation mechanism of paracrine factors is not well identified. Our group’s pilot results find that knockout MyD88 down-regulates HMGB1 expression, decreases p-STAT3 and VEGF production. But STAT3 over-expression of MSC could up-regulate the expression of VEGF and slow down I/R induced heart function decrease. Based on the results above, we hypothesize that MyD88 performs a beneficial role in MSC mediated cardioprotection via the HMGB1/p-STAT3 dependent pathway transcriptional induction of paracrine factors. To verify the hypothesis, we will make use of AMI model、I/R model and cell Hypoxia/ Reoxygenation model combined with gene silencing and cell cytokine chip technology to explore the intrinsic connections between MyD88、HMGB1 and STAT3, and their regulation role in paracrine factors transcription process, then to elucidate the molecular regulation mechanism of MyD88 pathway for paracrine factors release. This will further explain the inherent regulation network of the paracrine actions, search for new intervention targets and provide a new strategy for the treatment of AMI.

缺血再灌注损伤（I/R）是急性心梗（AMI）患者冠脉再通后的重要并发症，目前仍缺乏疗效确切的防治措施。骨髓间充质干细胞（BM-MSC）释放的旁分泌因子（VEGF、FGF和HGF等）能减轻I/R损伤改善心功能，但其确切释放调控机制不明。本课题发现敲减MyD88下调 HMGB1表达，降低p-STAT3和VEGF生成。而过表达STAT3则增加VEGF表达及延缓I/R致心功能衰减。由此我们假设MyD88通过HMGB1/p-STAT3途径调节旁分泌因子转录释放增加MSC介导的心脏保护作用。为验证此假说，本项目拟在AMI模型、I/R和细胞缺氧/复氧模型上，结合基因沉默、细胞因子芯片等技术，探讨MyD88、HMGB1与p-STAT3间的内在联系及在旁分泌因子转录中的调节作用，进而阐明MyD88调控旁分泌因子释放的分子机制。该研究将揭示旁分泌效应内在调控网络，寻找新的干预靶点，为临床AMI治疗提供新策略。

缺血再灌注损伤（I/R）是急性心肌梗死（AMI）患者冠脉再通后的重要并发症，目前仍缺乏疗效确切的防止措施。骨髓间充质干细胞（BM-MSC）释放的旁分泌因子（VEGF、FGF和HGF等）能减轻I/R损伤改善心功能，但其确切机制尚不明确。本课题主要研究HMGB1/STAT3信号通路在MSC发挥心肌细胞保护作用中的重要作用。我们的研究发现LPS作用MSC后旁分泌因子的释放以及HMGB1和STAT3的表达均显著上升，且沉默HMGB1和STAT3后均降低旁分泌因子的释放，减轻了MSC对心肌细胞的保护作用，使心肌细胞的凋亡率上升。这表明HMGB1/STAT3信号通路参与了MSC介导的心肌细胞保护作用，为寻找新的干预靶点提供新策略。此外，我们成功在体外建立了缺氧复氧模型，这为我们的实验以及为其他缺血再灌注损伤的研究者提供了体外模型建立的参考。