Institute for Advanced Medical Sciences, Hyogo Medical University (Nishinomiya Campus), 1-1 Mukogawacho, Nishinomiya 663-8501, Japan.
Department of Therapeutic Progress in Brain Diseases, Hyogo Medical University, 1-1 Mukogawacho, Nishinomiya 663-8501, Japan.
Cells. 2024 May 29;13(11):939. doi: 10.3390/cells13110939.
Increasing evidence shows that the administration of mesenchymal stem cells (MSCs) is a promising option for various brain diseases, including ischemic stroke. Studies have demonstrated that MSC transplantation after ischemic stroke provides beneficial effects, such as neural regeneration, partially by activating endogenous neural stem/progenitor cells (NSPCs) in conventional neurogenic zones, such as the subventricular and subgranular zones. However, whether MSC transplantation regulates the fate of injury-induced NSPCs (iNSPCs) regionally activated at injured regions after ischemic stroke remains unclear. Therefore, mice were subjected to ischemic stroke, and mCherry-labeled human MSCs (h-MSCs) were transplanted around the injured sites of nestin-GFP transgenic mice. Immunohistochemistry of brain sections revealed that many GFP cells were observed around the grafted sites rather than in the regions in the subventricular zone, suggesting that transplanted mCherry h-MSCs stimulated GFP locally activated endogenous iNSPCs. In support of these findings, coculture studies have shown that h-MSCs promoted the proliferation and neural differentiation of iNSPCs extracted from ischemic areas. Furthermore, pathway analysis and gene ontology analysis using microarray data showed that the expression patterns of various genes related to self-renewal, neural differentiation, and synapse formation were changed in iNSPCs cocultured with h-MSCs. We also transplanted h-MSCs (5.0 × 10 cells/µL) transcranially into post-stroke mouse brains 6 weeks after middle cerebral artery occlusion. Compared with phosphate-buffered saline-injected controls, h-MSC transplantation displayed significantly improved neurological functions. These results suggest that h-MSC transplantation improves neurological function after ischemic stroke in part by regulating the fate of iNSPCs.
越来越多的证据表明，间充质干细胞（MSCs）的给药是各种脑部疾病（包括缺血性中风）的一种有前途的选择。研究表明，缺血性中风后 MSC 移植提供了有益的效果，例如神经再生，部分是通过激活传统神经发生区域（如脑室下区和颗粒下区）中的内源性神经干细胞/祖细胞（NSPCs）。然而，MSC 移植是否调节缺血性中风后损伤诱导的 NSPCs（iNSPCs）的命运仍不清楚。因此，将 mCherry 标记的人 MSCs（h-MSCs）移植到 nestin-GFP 转基因小鼠的损伤部位周围，使小鼠发生缺血性中风。对脑切片进行免疫组织化学染色显示，在移植部位周围观察到许多 GFP 细胞，而不是在脑室下区的区域，这表明移植的 mCherry h-MSCs 刺激 GFP 局部激活内源性 iNSPCs。这些发现的支持证据表明，h-MSCs 促进了从缺血区域提取的 iNSPCs 的增殖和神经分化。此外，使用微阵列数据进行的通路分析和基因本体分析表明，与自我更新、神经分化和突触形成相关的各种基因的表达模式在与 h-MSCs 共培养的 iNSPCs 中发生了改变。我们还在大脑中动脉闭塞后 6 周将 h-MSCs（5.0×10^5 个细胞/µL）经颅移植到中风后小鼠的大脑中。与磷酸盐缓冲盐水注射对照相比，h-MSC 移植显著改善了神经功能。这些结果表明，h-MSC 移植通过调节 iNSPCs 的命运部分改善了缺血性中风后的神经功能。
