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Original Contribution

Postacute Stromal Cell–Derived Factor-1α Expression Promotes Neurovascular Recovery in Ischemic Mice

Yaning Li, Jun Huang, Xiaosong He, Guanghui Tang, Yao-Hui Tang, Yanqun Liu, Xiaojie Lin, Yifan Lu, Guo-Yuan Yang, Yongting Wang
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https://doi.org/10.1161/STROKEAHA.114.005078
Stroke. 2014;STROKEAHA.114.005078
Originally published May 13, 2014
Yaning Li
From the Neuroscience and Neuroengineering Research Center, Med-X Research Institute and School of Biomedical Engineering (Y.L., J.H., X.H., G.T., Y.-H.T., X.L., Y. Lu, G.-Y.Y., Y.W.) and Department of Neurology, Ruijin Hospital, School of Medicine (Y. Liu, G.-Y.Y.), Shanghai Jiao Tong University, Shanghai, China.
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Jun Huang
From the Neuroscience and Neuroengineering Research Center, Med-X Research Institute and School of Biomedical Engineering (Y.L., J.H., X.H., G.T., Y.-H.T., X.L., Y. Lu, G.-Y.Y., Y.W.) and Department of Neurology, Ruijin Hospital, School of Medicine (Y. Liu, G.-Y.Y.), Shanghai Jiao Tong University, Shanghai, China.
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Xiaosong He
From the Neuroscience and Neuroengineering Research Center, Med-X Research Institute and School of Biomedical Engineering (Y.L., J.H., X.H., G.T., Y.-H.T., X.L., Y. Lu, G.-Y.Y., Y.W.) and Department of Neurology, Ruijin Hospital, School of Medicine (Y. Liu, G.-Y.Y.), Shanghai Jiao Tong University, Shanghai, China.
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Guanghui Tang
From the Neuroscience and Neuroengineering Research Center, Med-X Research Institute and School of Biomedical Engineering (Y.L., J.H., X.H., G.T., Y.-H.T., X.L., Y. Lu, G.-Y.Y., Y.W.) and Department of Neurology, Ruijin Hospital, School of Medicine (Y. Liu, G.-Y.Y.), Shanghai Jiao Tong University, Shanghai, China.
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Yao-Hui Tang
From the Neuroscience and Neuroengineering Research Center, Med-X Research Institute and School of Biomedical Engineering (Y.L., J.H., X.H., G.T., Y.-H.T., X.L., Y. Lu, G.-Y.Y., Y.W.) and Department of Neurology, Ruijin Hospital, School of Medicine (Y. Liu, G.-Y.Y.), Shanghai Jiao Tong University, Shanghai, China.
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Yanqun Liu
From the Neuroscience and Neuroengineering Research Center, Med-X Research Institute and School of Biomedical Engineering (Y.L., J.H., X.H., G.T., Y.-H.T., X.L., Y. Lu, G.-Y.Y., Y.W.) and Department of Neurology, Ruijin Hospital, School of Medicine (Y. Liu, G.-Y.Y.), Shanghai Jiao Tong University, Shanghai, China.
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Xiaojie Lin
From the Neuroscience and Neuroengineering Research Center, Med-X Research Institute and School of Biomedical Engineering (Y.L., J.H., X.H., G.T., Y.-H.T., X.L., Y. Lu, G.-Y.Y., Y.W.) and Department of Neurology, Ruijin Hospital, School of Medicine (Y. Liu, G.-Y.Y.), Shanghai Jiao Tong University, Shanghai, China.
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Yifan Lu
From the Neuroscience and Neuroengineering Research Center, Med-X Research Institute and School of Biomedical Engineering (Y.L., J.H., X.H., G.T., Y.-H.T., X.L., Y. Lu, G.-Y.Y., Y.W.) and Department of Neurology, Ruijin Hospital, School of Medicine (Y. Liu, G.-Y.Y.), Shanghai Jiao Tong University, Shanghai, China.
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Guo-Yuan Yang
From the Neuroscience and Neuroengineering Research Center, Med-X Research Institute and School of Biomedical Engineering (Y.L., J.H., X.H., G.T., Y.-H.T., X.L., Y. Lu, G.-Y.Y., Y.W.) and Department of Neurology, Ruijin Hospital, School of Medicine (Y. Liu, G.-Y.Y.), Shanghai Jiao Tong University, Shanghai, China.
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Yongting Wang
From the Neuroscience and Neuroengineering Research Center, Med-X Research Institute and School of Biomedical Engineering (Y.L., J.H., X.H., G.T., Y.-H.T., X.L., Y. Lu, G.-Y.Y., Y.W.) and Department of Neurology, Ruijin Hospital, School of Medicine (Y. Liu, G.-Y.Y.), Shanghai Jiao Tong University, Shanghai, China.
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Abstract

Background and Purpose—Acute interventions of stroke are often challenged by a narrow treatment window. In this study, we explore treatments in the postacute phase of stroke with wider windows of opportunity. We investigated the effects of stromal cell–derived factor (SDF-1α) in neurovascular recovery during the postacute phase and downstream signaling pathways, underlying SDF-1α–mediated neurovascular recovery.

Methods—Adult male Institute of Cancer Research (ICR) mice underwent middle cerebral artery occlusion. One week after middle cerebral artery occlusion, the animals received stereotactic injection of adenoassociated virus (AAV) carrying SDF-1α gene as treatment or AAV-green fluorescent protein as control and were monitored for 5 weeks. Neurobehavioral outcomes were evaluated, and brain atrophy was measured. Neurogenesis and angiogenesis were examined. The proliferation and migration of neural progenitor cells were evaluated. Downstream pathways of SDF-1α were investigated. Inflammatory response was monitored.

Results—Neurobehavioral outcomes were improved, and brain atrophy was greatly reduced for ≤5 weeks in AAV-SDF-1α groups when compared with the control. SDF-1 receptor CXCR4 was upregulated and colocalized with neural and endothelial progenitor cells. The number of nestin+ and doublecortin+/bromodeoxyuridine+ cells in the subventricular zone, doublecortin+ and neuron+/bromodeoxyuridine+ cells in the perifocal region, and cluster of differentiation (CD)31+ and bromodeoxyuridine+/CD31+ microvessels are also significantly increased in AAV-SDF-1α groups. Administration of CXCR4 antagonist AMD3100 eliminated the beneficial effects of SDF-1α. SDF-1α/CXCR4 interaction activated AKT, extracellular signal-regulated kinases (ERK), and P38 mitogen-activated protein kinase (MAPK) signaling pathways but not the c-Jun N-terminal kinase (JNK) pathway.

Conclusions—SDF-1α promoted neurogenesis and angiogenesis during the postacute phase of ischemia without eliciting an inflammatory response. AAV-SDF-1α expression represents a promising avenue for ischemic stroke therapy with a wider treatment window.

  • angiogenesis effect
  • brain ischemia
  • chemokine CXCL12
  • genetic therapy
  • neurogenesis
  • Received February 7, 2014.
  • Revision received March 19, 2014.
  • Accepted April 8, 2014.
  • © 2014 American Heart Association, Inc.

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    Postacute Stromal Cell–Derived Factor-1α Expression Promotes Neurovascular Recovery in Ischemic Mice
    Yaning Li, Jun Huang, Xiaosong He, Guanghui Tang, Yao-Hui Tang, Yanqun Liu, Xiaojie Lin, Yifan Lu, Guo-Yuan Yang and Yongting Wang
    Stroke. 2014;STROKEAHA.114.005078, originally published May 13, 2014
    https://doi.org/10.1161/STROKEAHA.114.005078

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    Postacute Stromal Cell–Derived Factor-1α Expression Promotes Neurovascular Recovery in Ischemic Mice
    Yaning Li, Jun Huang, Xiaosong He, Guanghui Tang, Yao-Hui Tang, Yanqun Liu, Xiaojie Lin, Yifan Lu, Guo-Yuan Yang and Yongting Wang
    Stroke. 2014;STROKEAHA.114.005078, originally published May 13, 2014
    https://doi.org/10.1161/STROKEAHA.114.005078
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