Jiang Qi, Xue Shiyuan, Pan Xiaojing, Yu Tengbo, Wei Xinyi, Li Liping, Qi Chao, Shi Weipeng, Ren Zhongkai, Hu Die, Fu Haitao
Department of Sports Medicine, The Affiliated Hospital of Qingdao University, Qingdao, 266003, China.
Qingdao Medical College of Qingdao University, Qingdao University, Qingdao, 266071, China.
Sci Rep. 2025 Apr 21;15(1):13708. doi: 10.1038/s41598-025-98429-7.
Spinal cord injury (SCI) remains a significant therapeutic challenge, lacking effective treatment options. Related studies have found that neonatal microglia are more effective than adult microglia in promoting the recovery of SCI, but the reason why neonatal, not adult, microglia are more conducive to SCI recovery is not clear, the differences of gene expression and pathways between them are still worth exploring. Therefore, we examined changes in the microglial transcriptome after SCI in neonatal and adult mice. We identified hub genes or pathways that exhibited significant differential expression between the two groups. Four Gene sets were established for further analysis, named Gene set 1, Gene set 2, Gene set 3, Gene set 4, respectively. GO analysis revealed enrichment in categories critical for injury repair, including DNA metabolism, replication, recombination, meiotic cell cycle progression, regulation of cell-cell adhesion, megakaryocyte and endothelial development, modulation of the neuroinflammatory response, endocytosis, and regulation of cytokine production and cell migration. KEGG analysis revealed enrichment in pathways critical for various cellular processes, including the p53, TNF, PI3K-AKT, PPAR and B cell receptor signaling pathway, axon guidance, cytokine-cytokine receptor interaction. PPI and TF-hub gene-microRNA networks were constructed to elucidate the underlying gene regulatory mechanisms. Additionally, drug prediction was performed to identify potential therapeutic candidates. Finally, 11 hub genes (Chek1, RRM2, Lyve1, Mboat1, Clec4a3, Ccnd1, Cdk6, Zeb1, Igf1, Pparg, and Cd163) were selected from four Gene sets for further validation using qRT-PCR. We identified candidate genes and pathways involved in microglial transcriptome heterogeneity after SCI in neonatal and adult mice. These findings provide valuable insights into potential therapeutic targets for neonatal microglia in the treatment of SCI.
脊髓损伤（SCI）仍然是一个重大的治疗挑战，缺乏有效的治疗选择。相关研究发现，新生小胶质细胞在促进SCI恢复方面比成年小胶质细胞更有效，但新生小胶质细胞而非成年小胶质细胞更有利于SCI恢复的原因尚不清楚，它们之间基因表达和信号通路的差异仍值得探索。因此，我们研究了新生和成年小鼠SCI后小胶质细胞转录组的变化。我们确定了两组之间表现出显著差异表达的枢纽基因或信号通路。建立了四个基因集进行进一步分析，分别命名为基因集1、基因集2、基因集3、基因集4。基因本体（GO）分析显示，在对损伤修复至关重要的类别中存在富集，包括DNA代谢、复制、重组、减数分裂细胞周期进程、细胞间粘附调节、巨核细胞和内皮细胞发育、神经炎症反应调节、内吞作用以及细胞因子产生和细胞迁移的调节。京都基因与基因组百科全书（KEGG）分析显示，在对各种细胞过程至关重要的信号通路中存在富集，包括p53、肿瘤坏死因子（TNF）、磷脂酰肌醇-3激酶-蛋白激酶B（PI3K-AKT）、过氧化物酶体增殖物激活受体（PPAR）和B细胞受体信号通路、轴突导向、细胞因子-细胞因子受体相互作用。构建了蛋白质-蛋白质相互作用（PPI）和转录因子-枢纽基因-微小RNA网络，以阐明潜在的基因调控机制。此外，进行了药物预测以确定潜在的治疗候选物。最后，从四个基因集中选择了11个枢纽基因（Chek1、RRM2、Lyve1、Mboat1、Clec4a3、Ccnd1、Cdk6、Zeb1、Igf1、Pparg和Cd163），使用实时定量逆转录聚合酶链反应（qRT-PCR）进行进一步验证。我们确定了新生和成年小鼠SCI后参与小胶质细胞转录组异质性的候选基因和信号通路。这些发现为新生小胶质细胞治疗SCI的潜在治疗靶点提供了有价值的见解。
