He Jun, Luo Yuhan, Wang Chuang, Jiang Chonghua, Wang Jian, Xia Ying
Department of Neurosurgery, Haikou Affiliated Hospital of Central South University Xiangya School of Medicine, Haikou, Hainan Province, P. R. China.
The Second People's Hospital of Changde, Changde, Hunan Province, P. R. China.
CNS Neurosci Ther. 2025 Jun;31(6):e70463. doi: 10.1111/cns.70463.
BACKGROUND: Our previous study demonstrated that olfactory mucosa mesenchymal stem cell (OM-MSC) neuronal differentiation can reduce neural damage following intracerebral hemorrhage (ICH). However, the mechanisms that regulate OM-MSC neuronal differentiation to mitigate ICH-induced brain injury remain unclear. METHODS: The ICH model was established through autologous blood injection to evaluate the impact of OM-MSCs on brain injury, using the mNSS method, TUNEL, and Nissl staining, as well as the Western blot assay. qPCR, Western blotting, flow cytometry, and immunofluorescence assays were employed to assess the neuronal differentiation of OM-MSCs. The SUMOylation assay was conducted to investigate the relationship between IGF2BP2 and SENP1. RIP, RNA pull-down, and mRNA stability assays were performed to analyze the molecular interaction network involving SENP1, IGF2BP2, and SOX11. RESULTS: IGF2BP2 enhanced the protective effects of OM-MSCs against ICH-induced brain injury, as demonstrated by a significant reduction in brain edema, mNSS scores, and apoptosis, along with improved neuronal survival. Furthermore, the overexpression of IGF2BP2 increased the expression of Tuj-1, MAP2, NF200, and NeuN, while decreasing GFAP and ALDH1L1 levels, suggesting the stimulatory effects of IGF2BP2 on the neuronal differentiation of OM-MSCs. Mechanistically, SENP1 enhanced IGF2BP2 expression through SUMO1-induced IGF2BP2 SUMOylation. Additionally, IGF2BP2 functioned as an RNA-binding protein for SOX11, thereby increasing SOX11 levels. The depletion of IGF2BP2 negated the SENP1-induced neuronal differentiation of OM-MSCs. The overexpression of SOX11 mitigated the inhibitory effects of IGF2BP2 silencing on OM-MSC neuronal differentiation. CONCLUSION: The SENP1/IGF2BP2/SOX11 axis played a crucial role in the neuronal differentiation of OM-MSCs and ameliorated brain damage caused by ICH.
背景：我们之前的研究表明，嗅黏膜间充质干细胞（OM-MSC）向神经元的分化可减轻脑出血（ICH）后的神经损伤。然而，调节OM-MSC向神经元分化以减轻ICH诱导的脑损伤的机制仍不清楚。 方法：通过自体血注射建立ICH模型，使用改良神经功能缺损评分（mNSS）方法、TUNEL法、尼氏染色以及蛋白质免疫印迹法评估OM-MSC对脑损伤的影响。采用实时定量聚合酶链反应（qPCR）、蛋白质免疫印迹法、流式细胞术和免疫荧光测定法评估OM-MSC的神经元分化。进行SUMO化测定以研究胰岛素样生长因子2结合蛋白2（IGF2BP2）与小泛素样修饰蛋白特异性蛋白酶（SENP1）之间的关系。进行RNA免疫沉淀（RIP）、RNA下拉和mRNA稳定性测定以分析涉及SENP1、IGF2BP2和性别决定区Y框蛋白11（SOX11）的分子相互作用网络。 结果：IGF2BP2增强了OM-MSC对ICH诱导的脑损伤的保护作用，表现为脑水肿、mNSS评分和细胞凋亡显著降低，同时神经元存活率提高。此外，IGF2BP2的过表达增加了βIII微管蛋白（Tuj-1）、微管相关蛋白2（MAP2）、神经丝蛋白200（NF200）和神经元核抗原（NeuN）的表达，同时降低了胶质纤维酸性蛋白（GFAP）和醛脱氢酶1L1（ALDH1L1）水平，表明IGF2BP2对OM-MSC的神经元分化具有促进作用。机制上，SENP1通过SUMO1诱导的IGF2BP2 SUMO化增强了IGF2BP2的表达。此外，IGF2BP2作为SOX11的RNA结合蛋白发挥作用，从而增加SOX11水平。IGF2BP2的缺失消除了SENP1诱导的OM-MSC向神经元的分化。SOX11的过表达减轻了IGF2BP2沉默对OM-MSC神经元分化的抑制作用。 结论：SENP1/IGF2BP/SOX11轴在OM-MSC的神经元分化中起关键作用，并改善了ICH引起的脑损伤。
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