β1 integrin signaling promotes neuronal migration along vascular scaffolds in the post stroke brain

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    β1 integrin signaling promotes neuronal migration along vascular scaffolds in the post-stroke brain Teppei Fujioka, Naoko Kaneko, Itsuki Ajioka, Kanako Nakaguchi, Taichi Omata, Honoka Ohba, Reinhard Făassler, Jose Manuel Garca-Verdugo, Kiyotoshi Sekiguchi, Noriyuki Matsukawa, Kazunobu Sawamoto PII: DOI: Reference: S2352-3964(17)30005-1 doi:10.1016/j.ebiom.2017.01.005 EBIOM 909 To appear in: EBioMedicine Received date: Revised date: Accepted date: September 2016 23 December 2016 January 2017 Please cite this article as: Fujioka, Teppei, Kaneko, Naoko, Ajioka, Itsuki, Nakaguchi, Kanako, Omata, Taichi, Ohba, Honoka, Făassler, Reinhard, Garca-Verdugo, Jose Manuel, Sekiguchi, Kiyotoshi, Matsukawa, Noriyuki, Sawamoto, Kazunobu, β1 integrin signaling promotes neuronal migration along vascular scaffolds in the post-stroke brain, EBioMedicine (2017), doi:10.1016/j.ebiom.2017.01.005 This is a PDF file of an unedited manuscript that has been accepted for publication As a service to our customers we are providing this early version of the manuscript The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain ACCEPTED MANUSCRIPT PT β1 integrin signaling promotes neuronal migration along vascular scaffolds in SC RI the post-stroke brain Teppei Fujioka1,2, Naoko Kaneko1, Itsuki Ajioka3, Kanako Nakaguchi1, Taichi NU Omata1, Honoka Ohba1, Reinhard Fässler4, José Manuel García-Verdugo5,6, D MA Kiyotoshi Sekiguchi7, Noriyuki Matsukawa2 and Kazunobu Sawamoto1,8 TE 1) Department of Developmental and Regenerative Biology, Nagoya City Japan AC CE P University Graduate School of Medical Sciences, Nagoya, Aichi, 467-8601, 2) Department of Neurology and Neuroscience, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, 467-8601, Japan 3) Center for Brain Integration Research, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, 113-8510, Japan 4) Department of Molecular Medicine, Max Planck Institute of Biochemistry, Martinsried, 82152, Germany ACCEPTED MANUSCRIPT PT 5) Laboratorio de Neurobiología Comparada, Instituto Cavanilles, Universidad de RI Valencia, CIBERNED, Valencia, 46980, Spain SC 6) Unidad Mixta de Esclerosis Múltiple y Neurorregeneración, IIS Hospital La Fe, NU Valencia, 46026, Spain 7) Division of Matrixome Research and Application, Institute for Protein Research, MA Osaka University, Suita, Osaka, 565-0871, Japan D 8) Division of Neural Development and Regeneration, National Institute of TE Physiological Sciences, Okazaki, Aichi, 444-8585, Japan Professor AC CE P Corresponding author: Dr Kazunobu Sawamoto Department of Developmental and Regenerative Biology, Nagoya City University Graduate School of Medical Sciences Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan Phone: +81-52-853-8532 Fax: +81-52-851-1898 E-mail address: sawamoto@med.nagoya-cu.ac.jp ACCEPTED MANUSCRIPT RI PT Abstract SC Cerebral ischemic stroke is a main cause of chronic disability However, there is NU currently no effective treatment to promote recovery from stroke-induced neurological symptoms Recent studies suggest that after stroke, immature neurons, MA referred to as neuroblasts, generated in a neurogenic niche, the D ventricular-subventricular zone, migrate toward the injured area, where they TE differentiate into mature neurons Interventions that increase the number of AC CE P neuroblasts distributed at and around the lesion facilitate neuronal repair in rodent models for ischemic stroke, suggesting that promoting neuroblast migration in the post-stroke brain could improve efficient neuronal regeneration To move toward the lesion, neuroblasts form chain-like aggregates and migrate along blood vessels, which are thought to increase their migration efficiency However, the molecular mechanisms regulating these migration processes are largely unknown Here we studied the role of β1-class integrins, transmembrane receptors for extracellular matrix proteins, in these migrating neuroblasts We found that the neuroblast chain ACCEPTED MANUSCRIPT PT formation and blood vessel-guided migration critically depend on β1 integrin RI signaling β1 integrin facilitated the adhesion of neuroblasts to laminin and the SC efficient translocation of their soma during migration Moreover, artificial laminin-containing scaffolds promoted neuroblast chain formation and migration NU toward the injured area These data suggest that laminin signaling via β1 integrins MA supports vasculature-guided neuronal migration to efficiently supply neuroblasts to D injured areas This study also highlights the importance of vascular scaffolds for cell Key AC CE P TE migration in development and regeneration words: β1 integrin, Laminin, Vasculature-guided migration, Stroke Blood vessel, Chain migration, ACCEPTED MANUSCRIPT PT Highlights RI β1-class integrins facilitate blood vessel-guided neuronal migration in injured brain SC β1-class integrins induce laminin-dependent neuronal adhesion and somal NU translocation AC CE P TE D MA Laminin-containing artificial scaffolds promote neuronal migration ACCEPTED MANUSCRIPT PT Research in context RI Although stroke is a major cause of chronic disability, there are presently no SC effective treatments for promoting recovery after stroke Recent studies suggest NU that in the post-stroke brain, immature neurons generated in brain ventricle walls migrate and differentiate into mature neurons to functionally replace damaged MA neurons Fujioka et al demonstrate that β1-class integrin expressed in immature D neurons enables their migration along blood vessels, contributing to neuronal TE regeneration after stroke in mice Furthermore, laminin-containing scaffolds AC CE P promoted neuronal migration in culture and in injured brain tissue These findings elucidate the role of blood vessels as a scaffold for cell migration and regeneration Word count: 4,782 words ACCEPTED MANUSCRIPT RI PT Introduction SC Cerebral ischemic stroke causes marked neuronal loss in the brain, leading to NU various chronic disabilities in patients However, there is currently no effective treatment for the neurological symptoms in the post-stroke period MA Recent studies have revealed that neural stem/progenitor cells residing in the D ventricular-subventricular zone (V-SVZ) located at the lateral walls of lateral TE ventricles continuously generate new neurons in the adult mammalian brain (Ihrie AC CE P and Alvarez-Buylla, 2011) The immature new neurons, referred to as neuroblasts, have a capacity to migrate rapidly in the adult brain tissue toward the olfactory bulb (OB) through a route called the rostral migratory stream (RMS) After a stroke, some of the V-SVZ-derived neuroblasts migrate toward injured areas in the striatum through the complex and dense neuronal and glial network in the mature parenchyma, and differentiate into mature neurons, which are thought to functionally replace damaged neurons and improve neurological deficits (Lindvall and Kokaia, 2015) ACCEPTED MANUSCRIPT PT For their long-distance migration in brain tissue, neuroblasts use various RI scaffolds to reach their destination efficiently, where they mature and form neuronal SC networks In the developing neocortex, neuroblasts born in the ventricular zone NU migrate toward the upper layers using radial glial fibers as a scaffold, with which they interact through the adhesion molecule N-cadherin (Kawauchi et al., 2010) MA However, the radial glial fibers disappear within a few weeks of postnatal brain D development (Chanas-Sacre et al., 2000) In the adult brain, V-SVZ-derived TE neuroblasts form elongated chain-like clusters and use neighboring neurons as a AC CE P scaffold, occasionally contacting blood vessels for long-distance migration in the RMS (Bovetti et al., 2007; Snapyan et al., 2009; Whitman et al., 2009) and in post-stroke striatum toward the injured area (Kojima et al., 2010; Ohab et al., 2006; Yamashita et al., 2006; Zhang et al., 2009) The vasculature is important for providing a neurogenic niche for stem/progenitor cells and neuroblasts in the V-SVZ under physiological (Shen et al., 2008; Tavazoie et al., 2008; Mirzadeh et al., 2008) and post-stroke (Zhang et al., ... the content, and all legal disclaimers that apply to the journal pertain ACCEPTED MANUSCRIPT PT β1 integrin signaling promotes neuronal migration along vascular scaffolds in SC RI the post- stroke. ..  β1 integrin signaling promotes neuronal migration along vascular scaffolds in the post- stroke brain Teppei Fujioka, Naoko Kaneko, Itsuki Ajioka,... migration, Stroke Blood vessel, Chain migration, ACCEPTED MANUSCRIPT PT Highlights RI β1- class integrins facilitate blood vessel-guided neuronal migration in injured brain SC β1- class integrins