Wang Ying, Han Tianyu, Guo Ruocheng, Song Peiwen, Liu Yunlei, Wu Zuomeng, Ai Jichao, Shen Cailiang
Department of Medical Imaging, The First Affiliated Hospital of Anhui Medical University, Hefei, China.
Department of Orthopedics (Spinal Surgery), The First Affiliated Hospital of Anhui Medical University, Hefei, China.
Front Mol Neurosci. 2022 Mar 25;15:850364. doi: 10.3389/fnmol.2022.850364. eCollection 2022.
Spinal cord injury (SCI) often causes neuronal and axonal damage, resulting in permanent neurological impairments. Mesenchymal stem cells (MSCs) and extracellular vesicles (EVs) are promising treatments for SCI. However, the underlying mechanisms remain unclear. Herein, we demonstrated that EVs from bone marrow-derived MSCs promoted the differentiation of neural stem cells (NSCs) into the neurons and outgrowth of neurites that are extending into astrocytic scars in SCI rats. Further study found that let-7a-5p exerted a similar biological effect as MSC-EVs in regulating the differentiation of NSCs and leading to neurological improvement in SCI rats. Moreover, these MSC-EV-induced effects were attenuated by let-7a-5p inhibitors/antagomirs. When investigating the mechanism, bioinformatics predictions combined with western blot and RT-PCR analyses showed that both MSC-EVs and let-7a-5p were able to downregulate the expression of SMAD2 by inhibiting HMGA2. In conclusion, MSC-EV-secreted let-7a-5p promoted the regrowth of neurons and improved neurological recovery in SCI rats by targeting the HMGA2/SMAD2 axis.
脊髓损伤（SCI）常导致神经元和轴突损伤，造成永久性神经功能障碍。间充质干细胞（MSCs）和细胞外囊泡（EVs）是治疗SCI的有前景的方法。然而，其潜在机制仍不清楚。在此，我们证明来自骨髓间充质干细胞的细胞外囊泡促进神经干细胞（NSCs）向神经元分化以及轴突生长，轴突延伸至SCI大鼠的星形胶质瘢痕中。进一步研究发现，let-7a-5p在调节神经干细胞分化并导致SCI大鼠神经功能改善方面发挥了与间充质干细胞来源的细胞外囊泡类似的生物学效应。此外，这些间充质干细胞来源的细胞外囊泡诱导的效应被let-7a-5p抑制剂/拮抗剂减弱。在研究机制时，生物信息学预测结合蛋白质免疫印迹和逆转录-聚合酶链反应分析表明，间充质干细胞来源的细胞外囊泡和let-7a-5p均能够通过抑制HMGA2来下调SMAD2的表达。总之，间充质干细胞来源的细胞外囊泡分泌的let-7a-5p通过靶向HMGA2/SMAD2轴促进SCI大鼠神经元的再生并改善神经功能恢复。
