title: Intra-Arterial Transplantation of Allogeneic Mesenchymal Stem Cells Mounts Neuroprotective Effects in a Transient Ischemic Stroke Model in Rats: Analyses of Therapeutic Time Window and Its Mechanisms.
abstract: OBJECTIVE
  Intra-arterial stem cell transplantation exerts neuroprotective effects for ischemic stroke. However, the optimal therapeutic time window and mechanisms have not been completely understood. In this study, we investigated the relationship between the timing of intra-arterial transplantation of allogeneic mesenchymal stem cells (MSCs) in ischemic stroke model in rats and its efficacy in acute phase.
  
  
  METHODS
  Adult male Wistar rats weighing 200 to 250 g received right middle cerebral artery occlusion (MCAO) for 90 minutes. MSCs (1 × 10(6) cells/ 1 ml PBS) were intra-arterially injected at either 1, 6, 24, or 48 hours (1, 6, 24, 48 h group) after MCAO. PBS (1 ml) was intra-arterially injected to control rats at 1 hour after MCAO. Behavioral test was performed immediately after reperfusion, and at 3, 7 days after MCAO using the Modified Neurological Severity Score (mNSS). Rats were euthanized at 7 days after MCAO for evaluation of infarct volumes and the migration of MSCs. In order to explore potential mechanisms of action, the upregulation of neurotrophic factor and chemotactic cytokine (bFGF, SDF-1α) induced by cell transplantation was examined in another cohort of rats that received intra-arterial transplantation at 24 hours after recanalization then euthanized at 7 days after MCAO for protein assays.
  
  
  RESULTS
  Behavioral test at 3 and 7 days after transplantation revealed that stroke rats in 24h group displayed the most robust significant improvements in mNSS compared to stroke rats in all other groups (p's<0.05). Similarly, the infarct volumes of stroke rats in 24h group were much significantly decreased compared to those in all other groups (p's<0.05). These observed behavioral and histological effects were accompanied by MSC survival and migration, with the highest number of integrated MSCs detected in the 24h group. Moreover, bFGF and SDF-1α levels of the infarcted cortex were highly elevated in the 24h group compared to control group (p's<0.05).
  
  
  CONCLUSIONS
  These results suggest that intra-arterial allogeneic transplantation of MSCs provides post-stroke functional recovery and reduction of infarct volumes in ischemic stroke model of rats. The upregulation of bFGF and SDF-1α likely played a key mechanistic role in enabling MSC to afford functional effects in stroke. MSC transplantation at 24 hours after recanalization appears to be the optimal timing for ischemic stroke model, which should guide the design of clinical trials of cell transplantation for stroke patients.
authors.affiliation: Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1, Shikata-cho, Kita-ku, Okayama, 700-8558, Japan.
authors.forename: Atsuhiko
authors.initials: A
authors.lastname: Toyoshima
authors.affiliation: Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1, Shikata-cho, Kita-ku, Okayama, 700-8558, Japan.
authors.forename: Takao
authors.initials: T
authors.lastname: Yasuhara
authors.affiliation: Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1, Shikata-cho, Kita-ku, Okayama, 700-8558, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kameda
authors.affiliation: Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1, Shikata-cho, Kita-ku, Okayama, 700-8558, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Morimoto
authors.affiliation: Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1, Shikata-cho, Kita-ku, Okayama, 700-8558, Japan.
authors.forename: Hayato
authors.initials: H
authors.lastname: Takeuchi
authors.affiliation: Center for Innovative and Translational Medicine, Kochi University Medical School, Kohasu, Oko-cho, Nankoku, Kochi, 783-8505, Japan.
authors.forename: Feifei
authors.initials: F
authors.lastname: Wang
authors.affiliation: Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1, Shikata-cho, Kita-ku, Okayama, 700-8558, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Sasaki
authors.affiliation: Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1, Shikata-cho, Kita-ku, Okayama, 700-8558, Japan.
authors.forename: Susumu
authors.initials: S
authors.lastname: Sasada
authors.affiliation: Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1, Shikata-cho, Kita-ku, Okayama, 700-8558, Japan.
authors.forename: Aiko
authors.initials: A
authors.lastname: Shinko
authors.affiliation: Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1, Shikata-cho, Kita-ku, Okayama, 700-8558, Japan.
authors.forename: Takaaki
authors.initials: T
authors.lastname: Wakamori
authors.affiliation: Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1, Shikata-cho, Kita-ku, Okayama, 700-8558, Japan.
authors.forename: Mihoko
authors.initials: M
authors.lastname: Okazaki
authors.affiliation: Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1, Shikata-cho, Kita-ku, Okayama, 700-8558, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Kondo
authors.affiliation: Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1, Shikata-cho, Kita-ku, Okayama, 700-8558, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Agari
authors.affiliation: Department of Neurosurgery, University of South Florida College of Medicine, 12901 Bruce B Downs Blvd, Tampa, Florida, 33612, United States of America.
authors.forename: Cesario V
authors.initials: CV
authors.lastname: Borlongan
authors.affiliation: Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1, Shikata-cho, Kita-ku, Okayama, 700-8558, Japan.
authors.forename: Isao
authors.initials: I
authors.lastname: Date
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D020520:Brain Infarction / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D002465:Cell Movement; D058948:Cell Tracking; D018925:Chemokines / Q000378:metabolism; D004195:Disease Models, Animal; D002546:Ischemic Attack, Transient / Q000473:pathology* / Q000503:physiopathology* / Q000628:therapy; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000378:metabolism; D009414:Nerve Growth Factors / Q000378:metabolism; D051381:Rats; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D018925:Chemokines; D009414:Nerve Growth Factors