Zhang Qian, Chen Zhen-Wei, Zhao Yong-Hua, Liu Bo-Wen, Liu Nai-Wei, Ke Chien-Chih, Tan Hong-Mei
Cell Transplant. 2017 Feb 16;26(2):229-242. doi: 10.3727/096368916X693536. Epub 2016 Oct 21.
Being a potential candidate for stroke treatment, bone marrow-derived mesenchymal stem/stromal cells (BM-MSCs) have been demonstrated to be able to enhance angiogenesis and proliferation of reactive astrocytes, which subsequently leads to the amelioration of neurological injury. Increasing evidence further indicates that combining BM-MSCs with certain agents, such as simvastatin, may improve therapeutic effects. Sodium ferulate (SF) and n-butylidenephthalide (BP), two main components of Radix Angelica Sinensis, are proven to be important regulators of stem cells in cell migration, differentiation, and pluripotency maintenance. This study aimed to investigate whether combining BM-MSCs with SF and BP had better therapeutic effect in the treatment of stroke, and the underlying molecular basis for the therapeutic effects was also investigated. The results showed that combination treatment notably reduced neurological injury after stroke and increased the expression of astrocyte-derived vascular endothelial growth factor (VEGF), brain-derived neurotrophic factor (BDNF), and von Willebrand factor-positive vascular density in the ischemic boundary zone as evaluated by immunofluorescence staining. After treatment with BM-MSCs plus SF and BP, astrocytes showed increased expression of VEGF and BDNF by upregulating protein kinase B/mammalian target of rapamycin (AKT/mTOR) expression in an oxygen- and glucose-deprived (OGD) environment. Human umbilical vein endothelial cells (HUVECs) incubated with the conditioned medium (CM) derived from OGD astrocytes treated with BM-MSCs plus SF and BP showed significantly increased migration and tube formation compared with those incubated with the CM derived from OGD astrocytes treated with BM-MSCs alone. These results demonstrate that combination treatment enhances the expression of astrocyte-derived VEGF and BDNF, which contribute to angiogenesis after cerebral ischemia, and the underlying mechanism is associated with activation of the astrocytic AKT/mTOR signaling pathway. Our study provides a potential therapeutic approach for ischemic stroke.
作为中风治疗的潜在候选者，骨髓间充质干细胞（BM-MSCs）已被证明能够促进血管生成和反应性星形胶质细胞的增殖，进而改善神经损伤。越来越多的证据进一步表明，将BM-MSCs与某些药物（如辛伐他汀）联合使用可能会提高治疗效果。阿魏酸（SF）和正丁烯基苯酞（BP）是当归的两个主要成分，已被证明是干细胞在细胞迁移、分化和多能性维持方面的重要调节因子。本研究旨在探讨将BM-MSCs与SF和BP联合使用在中风治疗中是否具有更好的治疗效果，并研究其治疗效果的潜在分子基础。结果表明，联合治疗显著减轻了中风后的神经损伤，并通过免疫荧光染色评估发现，缺血边界区星形胶质细胞衍生的血管内皮生长因子（VEGF）、脑源性神经营养因子（BDNF）的表达以及血管性血友病因子阳性血管密度增加。在用BM-MSCs加SF和BP处理后，星形胶质细胞在氧糖剥夺（OGD）环境中通过上调蛋白激酶B/雷帕霉素哺乳动物靶点（AKT/mTOR）的表达，显示出VEGF和BDNF表达增加。与用单独BM-MSCs处理的OGD星形胶质细胞衍生的条件培养基（CM）孵育的人脐静脉内皮细胞（HUVECs）相比，用BM-MSCs加SF和BP处理的OGD星形胶质细胞衍生CM孵育的HUVECs显示出显著增加的迁移和管形成。这些结果表明，联合治疗增强了星形胶质细胞衍生的VEGF和BDNF的表达，这有助于脑缺血后的血管生成，其潜在机制与星形胶质细胞AKT/mTOR信号通路的激活有关。我们的研究为缺血性中风提供了一种潜在的治疗方法。
