间充质干细胞调节小胶质细胞极化对神经炎症反应的影响及机制研究

Microglia cells which are immune cells within the central nervous system play an important role in a variety of acute and chronic neurological diseases. Microglia cells have two main polarization states， M1 / M2, which play pro-inflammatory and anti-inflammatory effects. That’s why it might be a new way of treating neurological inflammatory diseases by regulating microglia polarization. The immune-modulatory and anti-inflammatory effects of of mesenchymal stem cells (MSCs) have drawn more and more attention of researchers. The preliminary study of project applicant has found that MSC has a role in regulating the inflammatory response of brain trauma model. And the follow-up study also found that BMSCs could inhibit the activation of NF-κB and MAPK signal transduction pathway in LPS-stimulated microglia by secretion of TSG-6, thereby reducing the expression of neuro-inflammatory factors in BV2 microglial cells. Previous studies focused mainly on the inhibition of M1 conversion in microglia cells to reduce inflammation. The study on how MSCs promote M2 transformation of the microglia cells was insufficient. Therefore, further study on how MSC regulate the M2 polarization of microglia cells and neurological restoration, can provide experiment base for applying MSC in the clinical treatment of central nervous system injury / inflammation-related diseases, and also provide new sights for the clinical treatment of related diseases.

小胶质细胞是神经系统内免疫细胞，在各种急慢性神经系统疾病发生及发展中发挥重要作用。小胶质细胞有M1/M2两种主要极化状态，分别发挥促炎和抗炎作用，因此调节小胶质细胞极化可能成为治疗神经炎症性疾病的新途径。间充质干细胞(MSC)免疫调节与抗炎作用受到越来越多的研究人员的关注。项目申报人前期研究发现，MSC在脑外伤模型具有调节炎症反应的作用，后续研究还发现，BMSCs可以通过分泌TSG-6来抑制LPS刺激后小胶质细胞NF-κB和MAPK信号传导通路的激活，从而减少BV2小胶质细胞神经炎性因子的表达。前期研究侧重于抑制小胶质细胞M1转化从而减少炎症，而对于MSC促进小胶质细胞M2转化研究不足。因此，进一步深入研究MSC调节小胶质细胞M2极化及其神经功能恢复影响，可为MSC日后用于临床治疗中枢神经系统损伤/炎症相关疾病提供实验依据,并为临床治疗相关疾病提供新思路。

小胶质细胞是中枢神经系统(CNS)中发挥免疫功能的细胞，在神经系统炎症相关疾病的发生发展中起着重要作用。间充质干细胞(mesenchymal stem cells，MSCs)在许多神经系统疾病中被证明可以促进功能恢复。其机制可能是通过多种可溶性因子降低炎症反应。其中，肿瘤坏死因子TNF-α诱导蛋白6(TSG-6)在骨髓间充质干细胞发挥的免疫调节作用中发挥关键作用，但其抗炎作用的确切机制尚不完全清楚。本研究中，首先我们证实MSCs可以抑制脂多糖(LPS)诱导的小鼠神经炎性反应。进一步在体内和体外，我们发现MSCs促进M2极化，抑制M1极化。此外，我们还证实了MSCs对小胶质细胞极化的影响依赖于TSG-6。本研究证实MSCs通过TSG-6促进小胶质细胞M2极化，从而发挥抑制神经炎症作用。