title: Postacute stromal cell-derived factor-1α expression promotes neurovascular recovery in ischemic mice.
abstract: OBJECTIVE
  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.
authors.affiliation: 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.
authors.forename: Yaning
authors.initials: Y
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Jun
authors.initials: J
authors.lastname: Huang
authors.affiliation: 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.
authors.forename: Xiaosong
authors.initials: X
authors.lastname: He
authors.affiliation: 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.
authors.forename: Guanghui
authors.initials: G
authors.lastname: Tang
authors.affiliation: 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.
authors.forename: Yao-Hui
authors.initials: YH
authors.lastname: Tang
authors.affiliation: 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.
authors.forename: Yanqun
authors.initials: Y
authors.lastname: Liu
authors.affiliation: 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.
authors.forename: Xiaojie
authors.initials: X
authors.lastname: Lin
authors.affiliation: 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.
authors.forename: Yifan
authors.initials: Y
authors.lastname: Lu
authors.affiliation: 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.
authors.forename: Guo-Yuan
authors.initials: GY
authors.lastname: Yang
authors.affiliation: 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. yongting.wang@gmail.com gyyang@sjtu.edu.cn.
authors.forename: Yongting
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000494:pharmacology; D001522:Behavior, Animal; D001596:Benzylamines; D054377:Chemokine CXCL12 / Q000096:biosynthesis* / Q000235:genetics; D000080027:Cyclams; D000229:Dependovirus; D000089662:Doublecortin Protein; D005786:Gene Expression Regulation; D015316:Genetic Therapy; D006571:Heterocyclic Compounds / Q000494:pharmacology; D020244:Infarction, Middle Cerebral Artery / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000235:genetics; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D018919:Neovascularization, Physiologic; D055495:Neurogenesis; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D019380:Anti-HIV Agents; D001596:Benzylamines; D054377:Chemokine CXCL12; C486264:Cxcr4 protein, rat; D000080027:Cyclams; C000714848:Dcx protein, rat; D000089662:Doublecortin Protein; D006571:Heterocyclic Compounds; D019718:Receptors, CXCR4; D051057:Proto-Oncogene Proteins c-akt; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C088327:plerixafor
keywords: angiogenesis effect; brain ischemia; chemokine CXCL12; genetic therapy; neurogenesis