Wnt5a-induced exosomes from bone marrow mesenchymal stem cells regulates immune cells via the NF-KB pathway, influencing neural stem cell proliferation and differentiation to promote spinal cord injury repair.

Spinal cord injury (SCI) remains a devastating neurological disorder with limited treatment options. Among emerging therapeutic strategies, the transplantation of mesenchymal stem cell-derived exosomes (MSC-Exos) has shown great promise owing to their functional consistency with donor cells, low immunogenicity, and suitability for various delivery routes. Wnt5a, a non-canonical Wnt ligand, has been reported to promote neuronal differentiation and spinal cord regeneration. However, its mechanistic role when delivered via exosomes (Exos) remains unclear. In the present study, the function and underlying mechanism of Wnt5a in promoting neuronal differentiation and spinal cord repair were investigated using bone marrow mesenchymal stem cell-derived exosomes (BMSC-Exos) in both in vitro and in vivo models. Our results demonstrated that Wnt5a-enriched BMSC-Exos significantly enhanced the proliferation and neuronal differentiation of neural stem cells, while suppressing astrocyte formation. High-throughput RNA sequencing revealed an association between Wnt5a and the nuclear factor-kB (NF-kB) signaling pathway. Intervention with lipopolysaccharide confirmed that Wnt5a exerts a suppressive effect on this pathway. In vivo, the transplantation of Wnt5a-modified BMSC-Exos facilitated the polarization of microglia toward an anti-inflammatory M2 phenotype, promoted neurogenesis, reduced astrocyte accumulation, improved spinal cord tissue architecture, and led to better motor function recovery. Collectively, these findings indicate that Wnt5a enhances the neuroregenerative potential of BMSC-Exos by modulating immune responses and suppressing neuroinflammation, likely through inhibiting the NF-kB signaling pathway. This strategy may offer a promising avenue for treating SCI脊髓损伤（Spinal cord injury, SCI）仍是一类具有毁灭性影响的神经系统疾病，当前可供选择的治疗手段十分有限。在诸多新兴治疗策略中，间充质干细胞来源外泌体（mesenchymal stem cell-derived exosomes, MSC-Exos）因与供体细胞功能一致性佳、免疫原性低且适配多种递送途径，展现出巨大的应用前景。Wnt5a作为一种非经典Wnt配体，已有研究证实其可促进神经元分化与脊髓再生，但经由外泌体递送时的具体作用机制仍未明确。本研究借助骨髓间充质干细胞来源外泌体（bone marrow mesenchymal stem cell-derived exosomes, BMSC-Exos），通过体外与体内模型，探究了Wnt5a在促进神经元分化与脊髓修复中的功能及潜在分子机制。研究结果显示，富集Wnt5a的BMSC-Exos可显著提升神经干细胞的增殖能力与神经元分化水平，同时抑制星形胶质细胞生成。高通量RNA测序分析显示，Wnt5a与核因子κB（nuclear factor-kB, NF-κB）信号通路存在调控关联；脂多糖干预实验证实，Wnt5a可对该通路发挥抑制作用。在体内模型中，移植经Wnt5a修饰的BMSC-Exos可促进小胶质细胞极化为抗炎M2表型，推动神经发生，减少星形胶质细胞聚集，改善脊髓组织结构，并有效改善运动功能恢复效果。综上，本研究结果表明，Wnt5a可通过抑制NF-κB信号通路，调节免疫应答并抑制神经炎症，从而增强BMSC-Exos的神经再生潜能。该策略有望为脊髓损伤的临床治疗提供极具前景的新途径。