Chondroitinase ABC combined with neural stem/progenitor cell transplantation enhances graft cell migration and outgrowth of growth-associated protein-43-positive fibers after rat spinal cord injury.
We previously reported that the transplantation of neural stem/progenitor cells (NSPCs) can contribute to the repair of injured spinal cord in adult rats and monkeys. In some cases, however, most of the transplanted cells adhered to the cavity wall and failed to migrate and integrate into the host spinal cord. In this study we focused on chondroitin sulfate proteoglycan (CSPG), a known constituent of glial scars that is strongly expressed after spinal cord injury (SCI), as a putative inhibitor of NSPC migration in vivo. We hypothesized that the digestion of CSPG by chondroitinase ABC (C-ABC) might promote the migration of transplanted cells and neurite outgrowth after SCI. An in vitro study revealed that the migration of NSPC-derived cells was inhibited by CSPG and that this inhibitory effect was attenuated by C-ABC pre-treatment. Consistently, an in vivo study of C-ABC treatment combined with NSPC transplantation into injured spinal cord revealed that C-ABC pre-treatment promoted the migration of the transplanted cells, whereas CSPG-immunopositive scar tissue around the lesion cavity prevented their migration into the host spinal cord in the absence of C-ABC pre-treatment. Furthermore, this combined treatment significantly induced the outgrowth of a greater number of growth-associated protein-43-positive fibers at the lesion epicentre, compared with NSPC transplantation alone. These findings suggested that the application of C-ABC enhanced the benefits of NSPC transplantation for SCI by reducing the inhibitory effects of the glial scar, indicating that this combined treatment may be a promising strategy for the regeneration of injured spinal cord.
Ikegami
Takeshi
T
Department of Orthopaedic Surgery, Keio University School of Medicine, Tokyo, Japan.
Nakamura
Masaya
M
Yamane
Junichi
J
Katoh
Hiroyuki
H
Okada
Seiji
S
Iwanami
Akio
A
Watanabe
Kota
K
Ishii
Ken
K
Kato
Fumikazu
F
Fujita
Hiroshi
H
Takahashi
Toyomi
T
Okano
Hirotaka James
HJ
Toyama
Yoshiaki
Y
Okano
Hideyuki
H
D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases; D000704:Analysis of Variance; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002465:Cell Movement / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D019765:Chondroitin ABC Lyase / Q000494:pharmacology*; D011508:Chondroitin Sulfate Proteoglycans / Q000378:metabolism / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004195:Disease Models, Animal; D004347:Drug Interactions; D019922:GAP-43 Protein / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology; D005904:Glial Fibrillary Acidic Protein; D007150:Immunohistochemistry / Q000379:methods; D007381:Intermediate Filament Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D064231:Nestin; D016900:Neurofilament Proteins; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013119:Spinal Cord Injuries / Q000601:surgery*; D033581:Stem Cell Transplantation / Q000379:methods*; D013234:Stem Cells / Q000187:drug effects* / Q000502:physiology; D013997:Time Factors; D014404:Tubulin
D011508:Chondroitin Sulfate Proteoglycans; D019922:GAP-43 Protein; D005904:Glial Fibrillary Acidic Protein; D007381:Intermediate Filament Proteins; D009419:Nerve Tissue Proteins; C577486:Nes protein, rat; D064231:Nestin; D016900:Neurofilament Proteins; D014404:Tubulin; D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases; D019765:Chondroitin ABC Lyase