Limb Remote Ischemic Conditioning Promotes Neurogenesis after Cerebral Ischemia by Modulating miR-449b/Notch1 Pathway in Mice.
Limb Remote Ischemic Conditioning Promotes Neurogenesis after Cerebral Ischemia by Modulating miR-449b/Notch1 Pathway in Mice.
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DOI：
10.3390/biom12081137
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发表时间：
2022-08-18
期刊：
影响因子：
5.5
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中科院分区：
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神经发生在中风患者的预后中起着重要作用，并且已知通过Notch 1信号通路的激活来促进。对气道上皮的研究表明，miR-449 b抑制Notch途径。本研究旨在研究肢体远程缺血条件处理（LRIC）是否能够促进脑缺血小鼠的神经发生，并研究miR-449 b/Notch 1通路在LRIC诱导的神经保护中的作用。对雄性C57 BL/6小鼠（22-25 g）进行短暂的大脑中动脉闭塞（MCAO），并且在MCA闭塞后立即在双侧下肢中进行LRIC。进行免疫荧光染色以评估神经发生。细胞系NE-4C用于阐明神经干细胞在8%O2中的增殖。在第28天LRIC治疗后，小鼠恢复神经功能。第7天，SVZ中神经元前体增殖增强，基底神经节中神经元前体迁移增强。LRIC在第28天促进小鼠神经功能的改善，促进SVZ中的神经元前体增殖，并在第7天增强基底神经节中的神经元前体迁移。神经功能评分与SVZ和纹状体中BrdU阳性/DCX阳性细胞数量呈负相关。LRIC促进SVZ中活化的Notch 1蛋白表达，并显著下调SVZ和血浆中的miR-449 b水平。在体外，发现miR-449 b靶向Notch 1。慢病毒介导的miR-449 b敲低增加了NE-4C细胞中的Notch 1水平，并增加了细胞的增殖。通过应用Notch 1 shRNA消除miR-449 b抑制对神经发生的影响。我们的研究表明，LRIC促进MCAO后神经干细胞的增殖和迁移，这些作用受到miR-449 b/Notch 1通路的调节。
Neurogenesis plays an important role in the prognosis of stroke patients and is known to be promoted by the activation of the Notch1 signaling pathway. Studies on the airway epithelium have shown that miR-449b represses the Notch pathway. The study aimed to investigate whether limb remote ischemic conditioning (LRIC) was able to promote neurogenesis in cerebral ischemic mice, and to investigate the role of the miR-449b/Notch1 pathway in LRIC-induced neuroprotection. Male C57BL/6 mice (22–25 g) were subjected to transient middle cerebral artery occlusion (MCAO), and LRIC was performed in the bilateral lower limbs immediately after MCA occlusion. Immunofluorescence staining was performed to assess neurogenesis. The cell line NE-4C was used to elucidate the proliferation of neuronal stem cells in 8% O2. After LRIC treatment on day 28, mice recovered neurological function. Neuronal precursor proliferation was enhanced in the SVZ, and neuronal precursor migration was enhanced in the basal ganglia on day 7. LRIC promoted the improvement of neurological function in mice on day 28, promoted neuronal precursor proliferation in the SVZ, and enhanced neuronal precursor migration in the basal ganglia on day 7. The neurological function score was negatively correlated with the number of BrdU-positive/DCX-positive cells in the SVZ and striatum. LRIC promoted activated Notch1 protein expression in the SVZ and substantially downregulated miR-449b levels in the SVZ and plasma. In vitro, miR-449b was found to target Notch1. Lentivirus-mediated miR-449b knockdown increased Notch1 levels in NE-4C cells and increased proliferation in the cells. The effects of miR-449b inhibition on neurogenesis were ablated by the application of Notch1 shRNA. Our study showed that LRIC promoted the proliferation and migration of neural stem cells after MCAO, and these effects were modulated by the miR-449b/Notch1 pathway.
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