Miyamoto Takuya, Kuboyama Kazuya, Honda Mizuki, Ohkawa Yasuyuki, Oki Shinya, Sawamoto Kazunobu
Department of Developmental and Regenerative Neurobiology, Institute of Brain Science, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
Department of Drug Discovery Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Front Neurosci. 2025 Jan 7;18:1504047. doi: 10.3389/fnins.2024.1504047. eCollection 2024.
In the ventricular-subventricular-zone (V-SVZ) of the postnatal mammalian brain, immature neurons (neuroblasts) are generated from neural stem cells throughout their lifetime. These V-SVZ-derived neuroblasts normally migrate to the olfactory bulb through the rostral migratory stream, differentiate into interneurons, and are integrated into the preexisting olfactory circuit. When the brain is injured, some neuroblasts initiate migration toward the lesion and attempt to repair the damaged neuronal circuitry, but their low regeneration efficiency prevents functional recovery. Elucidation of the molecular basis of neuroblast migration toward lesions is expected to lead to the development of new therapeutic strategies for brain regenerative medicine. Here, we show gene expression profiles of neuroblasts migrating in the peri-injured cortex compared with those migrating in the V-SVZ using photo-isolation chemistry, a method for spatial transcriptome analysis. Differentially expressed gene analysis showed that the expression levels of 215 genes (97 upregulated and 118 downregulated genes) were significantly different in neuroblasts migrating in the peri-injured cortex from those migrating in the V-SVZ. Gene Ontology analysis revealed that in neuroblasts migrating in the peri-injured cortex, expression of genes involved in regulating migration direction and preventing cell death was upregulated, while the expression of genes involved in cell proliferation and maintenance of the immature state was downregulated. Indeed, neuroblasts migrating in the peri-injured cortex had significantly lower Cyclin D2 mRNA and Ki67 protein expression levels than those in the V-SVZ. In the injured brain, amoeboid microglia/macrophages expressed transforming growth factor- (TGF-), and neuroblasts migrating in the peri-injured cortex expressed TGF- receptors. Experiments using primary cultured neuroblasts showed that application of TGF- significantly decreased proliferating cells labeled with BrdU. These data suggest that the proliferative activity of neuroblasts migrating toward lesions is suppressed by TGF- secreted from cells surrounding the lesion. This is the first comprehensive study characterizing the gene expression profiles of neuroblasts migrating in the peri-injured cortex.
在出生后哺乳动物大脑的脑室-脑室下区（V-SVZ），未成熟神经元（神经母细胞）在其整个生命周期中由神经干细胞产生。这些源自V-SVZ的神经母细胞通常通过吻侧迁移流迁移至嗅球，分化为中间神经元，并整合到预先存在的嗅觉回路中。当大脑受到损伤时，一些神经母细胞开始向损伤部位迁移，并试图修复受损的神经元回路，但其低再生效率阻碍了功能恢复。阐明神经母细胞向损伤部位迁移的分子基础有望推动脑再生医学新治疗策略的发展。在此，我们使用光隔离化学（一种空间转录组分析方法），展示了与在V-SVZ中迁移的神经母细胞相比，在损伤周围皮质中迁移的神经母细胞的基因表达谱。差异表达基因分析表明，在损伤周围皮质中迁移的神经母细胞与在V-SVZ中迁移的神经母细胞相比，215个基因（97个上调基因和118个下调基因）的表达水平存在显著差异。基因本体分析显示，在损伤周围皮质中迁移的神经母细胞中，参与调节迁移方向和防止细胞死亡的基因表达上调，而参与细胞增殖和维持未成熟状态的基因表达下调。事实上，在损伤周围皮质中迁移的神经母细胞的细胞周期蛋白D2 mRNA和Ki67蛋白表达水平明显低于V-SVZ中的神经母细胞。在受损大脑中，阿米巴样小胶质细胞/巨噬细胞表达转化生长因子-（TGF-），在损伤周围皮质中迁移的神经母细胞表达TGF-受体。使用原代培养神经母细胞的实验表明，应用TGF-可显著减少用溴脱氧尿苷标记的增殖细胞。这些数据表明，向损伤部位迁移的神经母细胞的增殖活性受到损伤周围细胞分泌的TGF-的抑制。这是第一项全面研究损伤周围皮质中迁移的神经母细胞基因表达谱的研究。
