维甲酸增强骨髓间充质干细胞免疫抑制和向少突胶质细胞分化的作用及其在治疗多发性硬化的研究

Our study confirmed that retinoic acid (RA) improved the expression of immunosuppressive marker of bone marrow mesenchymal stem cells (MSCs)and promoted MSCs to differentiate into oligodendrocyte precursor cells simultaneously. In pre-experiment, we also found that MSCs induced by RA differentiated and formed myelin after transplanted to the site of demyelination. Therefore, we hypothesize that the transplantation of MSCs induced by RA for multiple sclerosis(MS), can enhance immunosuppression to T cell of MSCs and reduce damage to myelin, promote more MSCs to differentiate into oligodendrocytes(Olig ) and form myelin, thereby improving neurological function of MS. To confirm this idea, we will build mouse model for MS, inject MSCs induced by RA intraventricularly, use RT-PCR, Western blot, flow cytometry , immunohistochemistry , immune electron microscopy techniques to observe immunosuppressive abilities and differentiation and myelin-formation of MSCs induced by RA. Immune suppression mechanism of RA on MSCs will be studied. We aim at obtaining evidences of enhancement of immunosuppression, reducing the destruction of myelin, increasing of differentiation into Olg and remyelination of MSCs induced by RA after transplanted into MS mice, which will providing new therapeutic strategies for the treatment of transplantation MSCs for MS in clinical.

我们已证实，维甲酸(RA)可同时提高骨髓间充质干细胞(MSCs)免疫抑制能力标记物表达，促进MSCs向少突胶质前体细胞分化，进一进预实验也发现，RA诱导的MSCs移植到脱髓鞘部位后能分化并形成髓鞘。因此，我们推测RA诱导的MSCs移植治疗多发性硬化(MS)，一方面增强MSCs对T细胞的抑制，减少髓鞘被继续破坏；另一方面促进更多的MSCs分化为少突胶质细胞(Olig)，形成髓鞘，从而改善MS的神经功能。为证实这一设想，我们将构建MS小鼠模型，脑室注射RA诱导的MSCs，采用RT-PCR、Western blot、流式细胞术、免疫组化、免疫电镜等技术，观察RA对MSCs免疫抑制能力及分化形成髓鞘的影响，并对RA影响MSCs免疫抑制能力的机制进行研究，旨在获得RA能增强MSCs的免疫抑制能力，减少髓鞘被破坏，增加向Olig分化及髓鞘化的证据，为临床移植MSCs治疗MS提供新的治疗策略。

肠道内有大量微生物，参与人体多种正常的生理代谢过程，和宿主保持一种互利共生关系。肠道菌群失调可能通过肠脑轴影响多发性硬化（MS），阿尔茨海默病（AD）等神经系统疾病，通过移植正常肠菌，恢复失调的菌群，可能是治疗MS，AD的有效方法。本项目通过粪菌移植（FMT）治疗MS小鼠及AD小鼠，发现FMT治疗后，MS小鼠神经功能评分、累积评分和发病率明显降低，而且发病时间延后，BBB通透性明显降低，髓鞘脱失改善，脑炎症减轻。AD小鼠小鼠的学习记忆能力更好，回肠及海马的Aβ1-42表达水平均显著降低。本项目结果提示FMT可能是治MS及AD 的有效手段。