Transforming growth factor α transforms astrocytes to a growth-supportive phenotype after spinal cord injury.
Astrocytes are both detrimental and beneficial for repair and recovery after spinal cord injury (SCI). These dynamic cells are primary contributors to the growth-inhibitory glial scar, yet they are also neuroprotective and can form growth-supportive bridges on which axons traverse. We have shown that intrathecal administration of transforming growth factor α (TGFα) to the contused mouse spinal cord can enhance astrocyte infiltration and axonal growth within the injury site, but the mechanisms of these effects are not well understood. The present studies demonstrate that the epidermal growth factor receptor (EGFR) is upregulated primarily by astrocytes and glial progenitors early after SCI. TGFα directly activates the EGFR on these cells in vitro, inducing their proliferation, migration, and transformation to a phenotype that supports robust neurite outgrowth. Overexpression of TGFα in vivo by intraparenchymal adeno-associated virus injection adjacent to the injury site enhances cell proliferation, alters astrocyte distribution, and facilitates increased axonal penetration at the rostral lesion border. To determine whether endogenous EGFR activation is required after injury, SCI was also performed on Velvet (C57BL/6J-Egfr(Vel)/J) mice, a mutant strain with defective EGFR activity. The affected mice exhibited malformed glial borders, larger lesions, and impaired recovery of function, indicating that intrinsic EGFR activation is necessary for neuroprotection and normal glial scar formation after SCI. By further stimulating precursor proliferation and modifying glial activation to promote a growth-permissive environment, controlled stimulation of EGFR at the lesion border may be considered in the context of future strategies to enhance endogenous cellular repair after injury.
Department of Physiology and Cell Biology, Center for Brain and Spinal Cord Repair, The Ohio State University, Columbus, Ohio 43210, USA.
Robin E
RE
White
Meghan
M
Rao
John C
JC
Gensel
Dana M
DM
McTigue
Brian K
BK
Kaspar
Lyn B
LB
Jakeman
D000704:Analysis of Variance; D000818:Animals; D001253:Astrocytes / Q000187:drug effects*; D001369:Axons / Q000187:drug effects / Q000502:physiology; D001973:Bromodeoxyuridine / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D054338:Cell Transdifferentiation / Q000187:drug effects* / Q000235:genetics; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D066246:ErbB Receptors / Q000172:deficiency / Q000378:metabolism; D005260:Female; D005727:Ganglia, Spinal / Q000166:cytology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D034882:Lamins / Q000378:metabolism; D008124:Locomotion / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058953:Neural Stem Cells / Q000187:drug effects; D016900:Neurofilament Proteins / Q000378:metabolism; D010641:Phenotype; D020127:Recovery of Function / Q000187:drug effects / Q000235:genetics; D013116:Spinal Cord / Q000166:cytology; D013119:Spinal Cord Injuries / Q000473:pathology* / Q000503:physiopathology / Q000628:therapy; D014162:Transfection / Q000379:methods; D016211:Transforming Growth Factor alpha / Q000235:genetics / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects* / Q000235:genetics
D005904:Glial Fibrillary Acidic Protein; D034882:Lamins; D016900:Neurofilament Proteins; D016211:Transforming Growth Factor alpha; C051774:neurofilament protein H; D049452:Green Fluorescent Proteins; C541485:EGFR protein, mouse; D066246:ErbB Receptors; D001973:Bromodeoxyuridine