title: The sonic hedgehog pathway mediates brain plasticity and subsequent functional recovery after bone marrow stromal cell treatment of stroke in mice.
abstract: Bone marrow stromal cells (MSCs) improve neurologic recovery after middle cerebral artery occlusion (MCAo). To examine whether in vivo blockage of the endogenous sonic hedgehog (Shh) pathway affects grafted MSC-induced neurologic benefits, MCAo mice were administered: vehicle (control); cyclopamine (CP)- a specific Shh pathway inhibitor; MSC; and MSC and cyclopamine (MSC-CP). Neurologic function was evaluated after MCAo. Electron microscopy and immunofluorescence staining were employed to measure synapse density, protein expression of tissue plasminogen activator (tPA), and Shh in parenchymal cells in the ischemic boundary zone (IBZ), respectively. Marrow stromal cell treatment significantly enhanced functional recovery after ischemia, concurrent with increases of synaptophysin, synapse density, and myelinated axons along the IBZ, and significantly increased tPA and Shh expression in astrocytes and neurons compared with control. After treatment with MSC-CP or CP, the above effects were reversed. Co-culture of MSCs with cortical neurons confirmed the effect of Shh on MSC-mediated neurite outgrowth. Our data support the hypothesis that the Shh pathway mediates brain plasticity via tPA and thereby functional recovery after treatment of stroke with MSCs.
authors.affiliation: Department of Pharmacology, Institute of Materia Medica, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, PR China.
authors.forename: Xiaoshuang
authors.initials: X
authors.lastname: Ding
authors.forename: Yi
authors.initials: Y
authors.lastname: Li
authors.forename: Zhongwu
authors.initials: Z
authors.lastname: Liu
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.forename: Yisheng
authors.initials: Y
authors.lastname: Cui
authors.forename: Xiaoguang
authors.initials: X
authors.lastname: Chen
authors.forename: Michael
authors.initials: M
authors.lastname: Chopp
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000648:ultrastructure; D018920:Coculture Techniques; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D020439:Growth Cones / Q000648:ultrastructure; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism*; D007150:Immunohistochemistry; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008854:Microscopy, Electron; D009473:Neuronal Plasticity / Q000502:physiology*; D009474:Neurons / Q000378:metabolism / Q000648:ultrastructure; D020127:Recovery of Function; D015398:Signal Transduction; D020521:Stroke / Q000378:metabolism / Q000628:therapy*; D016708:Synaptophysin / Q000096:biosynthesis; D010959:Tissue Plasminogen Activator / Q000096:biosynthesis; D014704:Veratrum Alkaloids / Q000494:pharmacology
chemical_list: D053823:Hedgehog Proteins; C465570:Shh protein, mouse; D016708:Synaptophysin; C569015:Syp protein, mouse; D014704:Veratrum Alkaloids; D010959:Tissue Plasminogen Activator; C000541:cyclopamine
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