间充质干细胞联合川芎嗪对多发性硬化症血脑屏障的保护作用及调节机制研究

Multiple sclerosis (MS) is the most common inflammatory and demyelinating disease of the central nervous system. To date, there is no ideal treatment for MS. Blood-brain barrier (BBB) disruption is a primary and crucial pathological characteristic of the MS. Inhibition of BBB disruption has been shown to attenuate the severity of MS. Our previous study has shown that mesenchymal stem cells (hMSCs) alleviated the severity of experimental autoimmune encephalomyelitis (EAE), an animal model of MS, by inhibiting BBB disruption. We also found that tetramethylpyrazine (TMP) promoted proliferation and differentiation of hMSCs, upregulated sphingosine 1-phosphate receptor 1(S1PR1) while downregulated S1PR2 expression in EAE mice and attenuated the severity of EAE. Most importantly, we found that hMSCs combined with TMP significantly decreased the clinical score of the EAE mice, compared with the single treatment. Based on these studies, in this project, we plan to further probe whether the combined theraphy function through preservation of the BBB integrity, explore whether S1PR1 and S1PR2 signaling are involved in modulating the effect on BBB protection by using an in vitro BBB permeability model. This study will not only illuminate the effect of this combined therapy on the EAE mice, but also provide experimental evidence for a novel experimental protocol to enhance the therapeutic effects in MS treatment.

多发性硬化症(MS)是中枢神经系统最主要的炎性、脱髓鞘疾病，目前尚无理想的治疗方案。血脑屏障(BBB)破坏是MS的重要病理特征，研究表明保护BBB能缓解其症状。前期研究发现，间充质干细胞(hMSCs)通过保护BBB缓解MS小鼠实验性自身免疫性脑脊髓炎(EAE)；川芎嗪(TMP)能促进hMSCs增殖和分化，上调1磷酸鞘氨醇受体1(S1PR1)而下调S1PR2在EAE小鼠的表达，通过保护BBB缓解EAE，且hMSCs联合TMP更显著降低EAE小鼠的神经行为学评分。项目在此基础上，拟进一步探讨hMSCs联合TMP保护BBB以缓解EAE的协同作用，并通过体外BBB通透模型，明确该联合治疗方案通过激活S1PR1、拮抗S1PR2信号通路调节对BBB保护作用的分子机制，探讨一种新的高效低毒的MS治疗方案，并为其临床应用提供实验依据。

多发性硬化是多发性硬化(MS)是中枢神经系统最主要的炎性、脱髓鞘疾病，目前尚无理想的治疗方案。炎症反应和血脑屏障(BBB)破坏是MS的重要病理特征，研究表明减少炎症反应和保护BBB能缓解其症状。我们前期研究发现川芎嗪(TMP)能够缓解MS小鼠模型实验性自身免疫性脑脊髓炎(EAE)，间充质干细胞(hMSCs)通过保护BBB缓解小鼠EAE。本项目通过建立EAE小鼠模型，明确了TMP可通过减少炎症反应，激活STAT3/SOCS3而抑制NF-кB信号通路促进活化的小胶质细胞由M1型向M2型分化保护BBB以缓解EAE；阐明了TMP通过改变脐带hMSCs(hUC-MSCs)的细胞周期，减少由氧化应激导致的活性氧产生和细胞凋亡来提高(hUC-MSCs)的疗效，并通过建立EAE小鼠模型，探讨了TMP预处理的hUC-MSCs比单纯的hUC-MSCs能更有效的改善EAE小鼠的行为学评分，减少炎症反应和BBB的破坏，从而缓解EAE。本项目实验结果为临床治疗MS提供一种新的高效低毒的治疗方案，并为其临床应用提供实验依据。