title: Time-dependent changes in the microenvironment of injured spinal cord affects the therapeutic potential of neural stem cell transplantation for spinal cord injury.
abstract: BACKGROUND
  The transplantation of neural stem/progenitor cells (NS/PCs) at the sub-acute phase of spinal cord injury, but not at the chronic phase, can promote functional recovery. However, the reasons for this difference and whether it involves the survival and/or fate of grafted cells under these two conditions remain unclear. To address this question, NS/PC transplantation was performed after contusive spinal cord injury in adult mice at the sub-acute and chronic phases.
  
  
  RESULTS
  Quantitative analyses using bio-imaging, which can noninvasively detect surviving grafted cells in living animals, revealed no significant difference in the survival rate of grafted cells between the sub-acute and chronic transplantation groups. Additionally, immunohistology revealed no significant difference in the differentiation phenotypes of grafted cells between the two groups. Microarray analysis revealed no significant differences in the expression of genes encoding inflammatory cytokines or growth factors, which affect the survival and/or fate of grafted cells, in the injured spinal cord between the sub-acute and chronic phases. By contrast, the distribution of chronically grafted NS/PCs was restricted compared to NS/PCs grafted at the sub-acute phase because a more prominent glial scar located around the lesion epicenter enclosed the grafted cells. Furthermore, microarray and histological analysis revealed that the infiltration of macrophages, especially M2 macrophages, which have anti-inflammatory role, was significantly higher at the sub-acute phase than the chronic phase. Ultimately, NS/PCs that were transplanted in the sub-acute phase, but not the chronic phase, promoted functional recovery compared with the vehicle control group.
  
  
  CONCLUSIONS
  The extent of glial scar formation and the characteristics of inflammation is the most remarkable difference in the injured spinal cord microenvironment between the sub-acute and chronic phases. To achieve functional recovery by NS/PC transplantation in cases at the chronic phase, modification of the microenvironment of the injured spinal cord focusing on glial scar formation and inflammatory phenotype should be considered.
authors.affiliation: Department of Orthopaedic Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo, 160-8582, Japan. hidokano@a2.keio.jp
authors.forename: Soraya
authors.initials: S
authors.lastname: Nishimura
authors.forename: Akimasa
authors.initials: A
authors.lastname: Yasuda
authors.forename: Hiroki
authors.initials: H
authors.lastname: Iwai
authors.forename: Morito
authors.initials: M
authors.lastname: Takano
authors.forename: Yoshiomi
authors.initials: Y
authors.lastname: Kobayashi
authors.forename: Satoshi
authors.initials: S
authors.lastname: Nori
authors.forename: Osahiko
authors.initials: O
authors.lastname: Tsuji
authors.forename: Kanehiro
authors.initials: K
authors.lastname: Fujiyoshi
authors.forename: Hayao
authors.initials: H
authors.lastname: Ebise
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Toyama
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Okano
authors.forename: Masaya
authors.initials: M
authors.lastname: Nakamura
mesh_terms: D000200:Action Potentials; D000208:Acute Disease; D000818:Animals; D001369:Axons / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation; D060833:Cellular Microenvironment; D002908:Chronic Disease; D002921:Cicatrix / Q000150:complications / Q000473:pathology / Q000503:physiopathology; D005260:Female; D008156:Luciferases / Q000378:metabolism; D008164:Luminescent Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity; D009186:Myelin Sheath / Q000378:metabolism / Q000473:pathology; D058953:Neural Stem Cells / Q000166:cytology*; D009457:Neuroglia / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D013119:Spinal Cord Injuries / Q000150:complications / Q000473:pathology* / Q000503:physiopathology / Q000628:therapy*; D033581:Stem Cell Transplantation; D013997:Time Factors
chemical_list: D008164:Luminescent Proteins; D008156:Luciferases