Endogenous stem cell proliferation induced by intravenous hedgehog agonist administration after contusion in the adult rat spinal cord.
OBJECTIVE
Sonic hedgehog (Shh) is a glycoprotein molecule that upregulates the transcription factor Gli1. The Shh protein plays a critical role in the proliferation of endogenous neural precursor cells when directly injected into the spinal cord after a spinal cord injury in adult rodents. Small-molecule agonists of the hedgehog (Hh) pathway were used in an attempt to reproduce these findings through intravenous administration.


METHODS
The expression of Gli1 was measured in rat spinal cord after the intravenous administration of an Hh agonist. Ten adult rats received a moderate contusion and were treated with either an Hh agonist (10 mg/kg, intravenously) or vehicle (5 rodents per group) 1 hour and 4 days after injury. The rats were killed 5 days postinjury. Tissue samples were immediately placed in fixative. Samples were immunohistochemically stained for neural precursor cells, and these cells were counted.


RESULTS
Systemic dosing with an Hh agonist significantly upregulated Gli1 expression in the spinal cord (p < 0.005). After spinal contusion, animals treated with the Hh agonist had significantly more nestin-positive neural precursor cells around the rim of the lesion cavity than in vehicle-treated controls (means +/- SDs, 46.9 +/- 12.9 vs 20.9 +/- 8.3 cells/hpf, respectively, p < 0.005). There was no significant difference in the area of white matter injury between the groups.


CONCLUSIONS
An intravenous Hh agonist at doses that upregulate spinal cord Gli1 transcription also increases the population of neural precursor cells after spinal cord injury in adult rats. These data support previous findings based on injections of Shh protein directly into the spinal cord.
Bambakidis
Nicholas C
NC
Department of Neurological Surgery, Case Western Reserve University School of Medicine, and Neurological Institute, University Hospitals Case Medical Center, Cleveland, Ohio, USA.
Horn
Eric M
EM
Nakaji
Peter
P
Theodore
Nicholas
N
Bless
Elizabeth
E
Dellovade
Tammy
T
Ma
Chiyuan
C
Wang
Xukui
X
Preul
Mark C
MC
Coons
Stephen W
SW
Spetzler
Robert F
RF
Sonntag
Volker K H
VK
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D003288:Contusions / Q000378:metabolism / Q000473:pathology* / Q000628:therapy*; D053823:Hedgehog Proteins / Q000008:administration & dosage / Q000819:agonists*; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D007381:Intermediate Filament Proteins / Q000378:metabolism; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D064231:Nestin; D051381:Rats; D017207:Rats, Sprague-Dawley; D013119:Spinal Cord Injuries / Q000378:metabolism / Q000473:pathology* / Q000628:therapy*; D013234:Stem Cells / Q000187:drug effects* / Q000502:physiology; D013904:Thoracic Vertebrae; D000071676:Zinc Finger Protein GLI1
C498521:Gli1 protein, rat; D053823:Hedgehog Proteins; D007381:Intermediate Filament Proteins; D051741:Kruppel-Like Transcription Factors; D009419:Nerve Tissue Proteins; C577486:Nes protein, rat; D064231:Nestin; D000071676:Zinc Finger Protein GLI1