Transplantation of ciliary neurotrophic factor-expressing adult oligodendrocyte precursor cells promotes remyelination and functional recovery after spinal cord injury.
Demyelination contributes to the dysfunction after traumatic spinal cord injury (SCI). We explored whether the combination of neurotrophic factors and transplantation of adult rat spinal cord oligodendrocyte precursor cells (OPCs) could enhance remyelination and functional recovery after SCI. Ciliary neurotrophic factor (CNTF) was the most effective neurotrophic factor to promote oligodendrocyte (OL) differentiation and survival of OPCs in vitro. OPCs were infected with retroviruses expressing enhanced green fluorescent protein (EGFP) or CNTF and transplanted into the contused adult thoracic spinal cord 9 d after injury. Seven weeks after transplantation, the grafted OPCs survived and integrated into the injured spinal cord. The survival of grafted CNTF-OPCs increased fourfold compared with EGFP-OPCs. The grafted OPCs differentiated into adenomatus polyposis coli (APC(+)) OLs, and CNTF significantly increased the percentage of APC(+) OLs from grafted OPCs. Immunofluorescent and immunoelectron microscopic analyses showed that the grafted OPCs formed central myelin sheaths around the axons in the injured spinal cord. The number of OL-remyelinated axons in ventrolateral funiculus (VLF) or lateral funiculus (LF) at the injured epicenter was significantly increased in animals that received CNTF-OPC grafts compared with all other groups. Importantly, 75% of rats receiving CNTF-OPC grafts recovered transcranial magnetic motor-evoked potential and magnetic interenlargement reflex responses, indicating that conduction through the demyelinated axons in VLF or LF, respectively, was partially restored. More importantly, recovery of hindlimb locomotor function was significantly enhanced in animals receiving grafts of CNTF-OPCs. Thus, combined treatment with OPC grafts expressing CNTF can enhance remyelination and facilitate functional recovery after traumatic SCI.
Cao
Qilin
Q
Kentucky Spinal Cord Injury Research Center, University of Louisville School of Medicine, Louisville, Kentucky 40202, USA. qi-lin.cao@uth.tmc.edu
He
Qian
Q
Wang
Yaping
Y
Cheng
Xiaoxin
X
Howard
Russell M
RM
Zhang
Yiping
Y
DeVries
William H
WH
Shields
Christopher B
CB
Magnuson
David S K
DS
Xu
Xiao-Ming
XM
Kim
Dong H
DH
Whittemore
Scott R
SR
D025601:Adenomatous Polyposis Coli Protein / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D020934:Ciliary Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D003711:Demyelinating Diseases / Q000378:metabolism / Q000503:physiopathology / Q000601:surgery; D004195:Disease Models, Animal; D019054:Evoked Potentials, Motor / Q000502:physiology; D005260:Female; D005822:Genetic Vectors / Q000235:genetics; D006085:Graft Survival / Q000502:physiology; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D009186:Myelin Sheath / Q000378:metabolism / Q000648:ultrastructure; D009416:Nerve Regeneration / Q000502:physiology; D009431:Neural Conduction / Q000502:physiology; D009836:Oligodendroglia / Q000378:metabolism*; D010243:Paralysis / Q000209:etiology / Q000503:physiopathology / Q000601:surgery; D051381:Rats; D011916:Rats, Inbred F344; D020127:Recovery of Function / Q000502:physiology; D013116:Spinal Cord / Q000473:pathology / Q000503:physiopathology / Q000601:surgery*; D013119:Spinal Cord Injuries / Q000473:pathology / Q000503:physiopathology / Q000601:surgery*; D033581:Stem Cell Transplantation / Q000379:methods*; D013234:Stem Cells / Q000378:metabolism*; D014162:Transfection; D016896:Treatment Outcome
D025601:Adenomatous Polyposis Coli Protein; D020934:Ciliary Neurotrophic Factor; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins