Abstract：
Bone marrow mesenchymal stem cells (BMSCs) have therapeutic potential in the subacute/chronic phase of acute ischemic stroke (AIS), but the underlying mechanisms are not yet fully elucidated. There is a knowledge gap in understanding the metabolic mechanisms of BMSCs in stroke therapy. In this study, we administered BMSCs intravenously 24 h after reperfusion in rats with transient cerebral artery occlusion (MCAO). The treatment with BMSCs for 21 days significantly reduced the modified neurological severity score of MCAO rats (P < 0.01) and increased the number of surviving neurons in both the striatum and hippocampal dentate gyrus region (P < 0.01, respectively). Moreover, BMSCs treatment resulted in significant enhancements in various structural parameters of dendrites in layer V pyramidal neurons in the injured hemispheric motor cortex, including total length (P < 0.05), number of branches (P < 0.05), number of intersections (P < 0.01), and spine density (P < 0.05). Then, we performed plasma untargeted metabolomics analysis to study the metabolic changes of BMSCs on AIS. There were 65 differential metabolites identified in the BMSCs treatment group. Metabolic profiling analysis revealed that BMSCs modulate abnormal sphingolipid metabolism and glycerophospholipid metabolism, particularly affecting core members such as sphingomyelin (SM), ceramide (Cer) and sphingosine-1-phosphate (S1P). The metabolic network analysis and pathway-based compound-reaction-enzyme-gene network analysis showed that BMSCs inhibited the Cer-induced apoptotic pathway and promoted the S1P signaling pathway. These findings suggest that the enhanced effects of BMSCs on neuronal survival and synaptic plasticity after stroke may be mediated through these pathways. In conclusion, our study provides novel insight into the potential mechanisms of BMSCs treatment in stroke and sheds light on the possible clinical translation of BMSCs.
摘要：
骨髓间充质干细胞(BMSCs)在急性缺血性卒中(AIS)的亚急性/慢性期具有治疗潜力,但是潜在的机制尚未完全阐明。在了解BMSCs在中风治疗中的代谢机制方面存在知识空白。在这项研究中,我们在短暂性脑动脉闭塞（MCAO）大鼠再灌注后24小时静脉注射BMSCs。用BMSCs治疗21天可显著降低MCAO大鼠的神经功能缺损程度评分（P<0.01），增加纹状体和海马齿状回区存活神经元的数量（分别为P<0.01）。此外，BMSCs治疗导致受损的半球运动皮质V层锥体细胞树突的各种结构参数显着增强，包括总长度（P<0.05），分支数（P<0.05），交叉口数(P<0.01),脊柱密度(P<0.05)。然后，我们进行血浆非靶向代谢组学分析以研究BMSCs在AIS上的代谢变化。在BMSCs治疗组中鉴定出65种差异代谢物。代谢谱分析显示BMSCs调节异常的鞘脂代谢和甘油磷脂代谢,特别是影响核心成员，如鞘磷脂(SM)，神经酰胺（Cer）和鞘氨醇-1-磷酸（S1P）。代谢网络分析和基于通路的复合-反应-酶-基因网络分析显示BMSCs抑制Cer诱导的凋亡通路,促进S1P信号通路。这些发现表明，中风后BMSCs对神经元存活和突触可塑性的增强作用可能是通过这些途径介导的。总之,我们的研究为BMSCs治疗中风的潜在机制提供了新的见解，并阐明了BMSCs可能的临床翻译。
