Zeb2/Axin2-Enriched BMSC-Derived Exosomes Promote Post-Stroke Functional Recovery by Enhancing Neurogenesis and Neural Plasticity
Zeb2/Axin2-Enriched BMSC-Derived Exosomes Promote Post-Stroke Functional Recovery by Enhancing Neurogenesis and Neural Plasticity
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DOI：
10.1007/s12031-021-01887-7
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发表时间：
2021-08-16
影响因子：
3.1
通讯作者：
Zhang, Wei
中科院分区：
文献类型：
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作者：
Wei, Rui;Zhang, Lin;Zhang, Wei
从骨髓来源的间充质基质细胞（BMSCs）中收获的外泌体已显示出在许多疾病中的治疗潜力。在体外，Zeb 2/Axin 2刺激内源性神经发生，从而诱导中风后的功能恢复。在这里，我们研究了从用Zeb 2/Axin 2过表达质粒转染的BMSC收获的富含Zeb 2/Axin 2的外泌体是否会增强神经恢复。与对照相比，两种外泌体治疗均显著改善了功能恢复，并且在大脑中动脉闭塞MCAO大鼠模型中，与对照BMSC外泌体治疗相比，富含Zeb 2/Axin 2的外泌体对神经功能、神经发生和神经突重塑/神经元树突可塑性具有显著更好的改善效果。在用富含Zeb 2/Axin 2的BMSC exosomes刺激后，MCAO大鼠的空间记忆和神经功能显示出显著的恢复。脑室下区（SVZ）、海马和皮质区神经元数量增加，神经生长因子（NGF、BDNF等）表达减少。被上调了在缺血边界区，富含Zeb 2/Axin 2的外泌体通过增加突触数量促进突触重塑，并逆转缺血损伤引起的磷酸化神经丝（SMI-31）和突触素（SYN）的轴突丢失，从而减轻轴突死亡并促进突触增殖。在体外，富含Zeb 2/Axin 2的外泌体显著增加了缺氧缺糖（OGD）条件下培养的皮质胚胎大鼠神经元的轴突分支和伸长。此外，富含Ex-Zeb 2/Axin 2的外泌体下调SOX 10、内皮素-3/EDNRB和Wnt/β-连环蛋白表达的蛋白水平。结论：从Ex-Zeb 2/Axin 2 BMSC中提取的exosomes可通过促进神经干细胞的增殖和分化，改善脑梗死后神经可塑性和功能恢复。其机制可能与SOX 10、Wnt/β-catenin和内皮素-3/EDNRB通路有关。
Exosomes harvested from bone marrow-derived mesenchymal stromal cells (BMSCs) have shown treatment potential in many diseases. In vitro, Zeb2/Axin2 stimulated endogenous neurogenesis, which induced functional recovery after stroke. Here, we investigated whether the Zeb2/Axin2-enriched exosomes harvested from BMSCs transfected with a Zeb2/Axin2 overexpression plasmid would enhance neurological recovery. Compared with the control, both exosome treatments significantly improved functional recovery, and Zeb2/Axin2-enriched exosomes had significantly more improved effects on neurological function, neurogenesis, and neurite remodeling/neuronal dendrite plasticity than the control BMSC exosome treatment in a middle cerebral artery occlusion MCAO rat model. After stimulation with Zeb2/Axin2-enriched BMSC exosomes, the spatial memory and nerve function of MCAO rats showed marked recovery. The number of neurons was increased in the subventricular zone (SVZ), hippocampus, and cortex area, while the expression of nerve growth factors (NGF, BDNF, etc.) was upregulated. In the ischemic boundary zone, Zeb2/Axin2-enriched exosomes promoted synaptic remodeling by increasing the number of synapses and reversed the axonal loss of phosphorylated neurofilament (SMI-31) and synaptophysin (SYN) caused by ischemic injury, thus alleviating axonal demise and promoting synaptic proliferation. In vitro, Zeb2/Axin2-enriched exosomes significantly increased neurite branching and elongation of cultured cortical embryonic rat neurons under oxygen- and glucose-deprived (OGD) conditions. Moreover, Ex-Zeb2/Axin2-enriched exosomes downregulated the protein level of SOX10, endothelin-3/EDNRB, and Wnt/beta-catenin expression. In conclusion, exosomes harvested from Ex-Zeb2/Axin2 BMSC could improve post-stroke neuroplasticity and functional recovery in MCAO rats by promoting proliferation and differentiation of neural stem cells. The mechanism may be related to the SOX10, Wnt/beta-catenin, and endothelin-3/EDNRB pathways.