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/β-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/β-catenin, and endothelin-3/EDNRB pathways.

从骨髓来源的间充质基质细胞 (BMSC) 中提取的外泌体已显示出在许多疾病中的治疗潜力。在体外，Zeb2/Axin2 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 Zeb2/Axin2 过表达质粒转染的 BMSC 中收获的富含 Zeb2/Axin2 的外泌体是否会增强神经功能恢复。与对照组相比，两种外泌体治疗均显着改善了功能恢复，并且在大脑中动脉闭塞中，富含 Zeb2/Axin2 的外泌体对神经功能、神经发生和神经突重塑/神经元树突可塑性的影响明显优于对照组 BMSC 外泌体治疗MCAO 大鼠模型。在用富含 Zeb2/Axin2 的 BMSC 外泌体刺激后，MCAO大鼠的空间记忆和神经功能明显恢复。脑室下区（SVZ）、海马和皮层区域的神经元数量增加，而神经生长因子（NGF、BDNF等）的表达上调。在缺血边界区，富含 Zeb2/Axin2 的外泌体通过增加突触数量促进突触重塑，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，从而缓解轴突死亡，促进突触增殖。在体外，在缺氧和缺糖 (OGD) 条件下，富含 Zeb2/Axin2 的外泌体显着增加了培养的皮层胚胎大鼠神经元的神经突分支和伸长。此外，富含 Ex-Zeb2/Axin2 的外泌体下调了 SOX10 的蛋白质水平，内皮素-3/EDNRB 和 Wnt/β-连环蛋白表达。总之，从 Ex-Zeb2/Axin2 BMSC 收获的外泌体可以通过促进神经干细胞的增殖和分化来改善 MCAO 大鼠的中风后神经可塑性和功能恢复。其机制可能与 SOX10、Wnt/β-catenin 和内皮素-3/EDNRB 通路有关。