Limb Remote Ischemic Conditioning Promotes Neurogenesis after Cerebral Ischemia by Modulating miR-449b/Notch1 Pathway in Mice
Sijie Li,
Yong Yang,
Ning Li,
Haiyan Li,
Jiali Xu,
Wenbo Zhao,
Xiaojie Wang,
Linqing Ma,
Chen Gao,
Yuchuan Ding,
Xunming Ji,
Changhong Ren
Affiliations
Sijie Li
Beijing Key Laboratory of Hypoxia Translational Medicine, Xuanwu Hospital, Center of Stroke, Beijing Institute of Brain Disorder, Capital Medical University, Beijing 100053, China
Yong Yang
School of Traditional Chinese Medicine, Beijing University of Chines Medicine, Beijing 100029, China
Ning Li
Beijing Key Laboratory of Hypoxia Translational Medicine, Xuanwu Hospital, Center of Stroke, Beijing Institute of Brain Disorder, Capital Medical University, Beijing 100053, China
Haiyan Li
Beijing Key Laboratory of Hypoxia Translational Medicine, Xuanwu Hospital, Center of Stroke, Beijing Institute of Brain Disorder, Capital Medical University, Beijing 100053, China
Jiali Xu
Beijing Key Laboratory of Hypoxia Translational Medicine, Xuanwu Hospital, Center of Stroke, Beijing Institute of Brain Disorder, Capital Medical University, Beijing 100053, China
Wenbo Zhao
Beijing Key Laboratory of Hypoxia Translational Medicine, Xuanwu Hospital, Center of Stroke, Beijing Institute of Brain Disorder, Capital Medical University, Beijing 100053, China
Xiaojie Wang
Department of Neurology, Shenzhen Qianhai Shekou Free Trade Zone Hospital, Shenzhen 518054, China
Linqing Ma
Department of Neurology, The People’s Hospital of Suzhou New District, Suzhou 215129, China
Chen Gao
Beijing Key Laboratory of Hypoxia Translational Medicine, Xuanwu Hospital, Center of Stroke, Beijing Institute of Brain Disorder, Capital Medical University, Beijing 100053, China
Yuchuan Ding
Department of Neurosurgery, Wayne State University School of Medicine, Detroit, MI 48201, USA
Xunming Ji
Beijing Key Laboratory of Hypoxia Translational Medicine, Xuanwu Hospital, Center of Stroke, Beijing Institute of Brain Disorder, Capital Medical University, Beijing 100053, China
Changhong Ren
Beijing Key Laboratory of Hypoxia Translational Medicine, Xuanwu Hospital, Center of Stroke, Beijing Institute of Brain Disorder, Capital Medical University, Beijing 100053, China
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.
