Adenovirus vector-mediated ex vivo gene transfer of brain-derived neurotrophic factor to bone marrow stromal cells promotes axonal regeneration after transplantation in completely transected adult rat spinal cord.
The aim of this study was to evaluate the efficacy in adult rat completely transected spinal cord of adenovirus vector-mediated brain-derived neurotrophic factor (BDNF) ex vivo gene transfer to bone marrow stromal cells (BMSC). BMSC were infected with adenovirus vectors carrying beta-galactosidase (AxCALacZ) or BDNF (AxCABDNF) genes. The T8 segment of spinal cord was removed and replaced by graft containing Matrigel alone (MG group) or Matrigel and BMSC infected by AxCALacZ (BMSC-LacZ group) or AxCABDNF (BMSC-BDNF group). Axons in the graft were evaluated by immunohistochemistry and functional recovery was assessed with BBB locomotor scale. In the BMSC-BDNF group, the number of fibers positive for growth associated protein-43, tyrosine hydroxylase, and calcitonin gene-related peptide was significantly larger than numbers found for the MG and BMSC-LacZ groups. Rats from BMSC-BDNF and BMSC-LacZ groups showed significant recovery of hind limb function compared with MG rats; however, there was no significant difference between groups in degree of functional recovery. These findings demonstrate that adenovirus vector-mediated ex vivo gene transfer of BDNF enhances the capacity of BMSC to promote axonal regeneration in this completely transected spinal cord model; however, BDNF failed to enhance hind limb functional recovery. Further investigation is needed to establish an optimal combination of cell therapy and neurotrophin gene transfer for cases of spinal cord injury.
Koda
Masao
M
Department of Orthopaedic Surgery, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan. m-koda@bb.em-net.ne.jp
Kamada
Takahito
T
Hashimoto
Masayuki
M
Murakami
Masazumi
M
Shirasawa
Hiroshi
H
Sakao
Seiichiro
S
Ino
Hidetoshi
H
Yoshinaga
Katsunori
K
Koshizuka
Shuhei
S
Moriya
Hideshige
H
Yamazaki
Masashi
M
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism / Q000821:virology; D016026:Bone Marrow Transplantation / Q000379:methods*; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000235:genetics; D020439:Growth Cones / Q000378:metabolism / Q000648:ultrastructure; D008297:Male; D009416:Nerve Regeneration / Q000235:genetics; D009473:Neuronal Plasticity / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D020127:Recovery of Function / Q000235:genetics; D013119:Spinal Cord Injuries / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy*; D017154:Stromal Cells / Q000378:metabolism / Q000637:transplantation* / Q000821:virology; D016896:Treatment Outcome
D019208:Brain-Derived Neurotrophic Factor