The hematopoietic factor granulocyte-colony stimulating factor improves outcome in experimental spinal cord injury.
Granulocyte-colony stimulating factor (G-CSF) is a potent hematopoietic factor that drives differentiation of neutrophilic granulocytes. We have recently shown that G-CSF also acts as a neuronal growth factor, protects neurons in vitro and in vivo, and has regenerative potential in various neurological disease models. Spinal cord injury (SCI) following trauma or secondary to skeletal instability is a terrible condition with no effective therapies available at present. In this study, we show that the G-CSF receptor is up-regulated upon experimental SCI and that G-CSF improves functional outcome in a partial dissection model of SCI. G-CSF significantly decreases apoptosis in an experimental partial spinal transsection model in the mouse and increases expression of the anti-apoptotic G-CSF target gene Bcl-X(L). In vitro, G-CSF enhances neurite outgrowth and branching capacity of hippocampal neurons. In vivo, G-CSF treatment results in improved functional connectivity of the injured spinal cord as measured by Mn(2+)-enhanced MRI. G-CSF also increased length of the dorsal corticospinal tract and density of serotonergic fibers cranial to the lesion center. Mice treated systemically with G-CSF as well as transgenic mice over-expressing G-CSF in the CNS exhibit a strong improvement in functional outcome as measured by the BBB score and gridwalk analysis. We show that G-CSF improves outcome after experimental SCI by counteracting apoptosis, and enhancing connectivity in the injured spinal cord. We conclude that G-CSF constitutes a promising and feasible new therapy option for SCI.
Pitzer
Claudia
C
Sygnis Bioscience, Im Neuenheimer Feld, Heidelberg, Germany.
Klussmann
Stefan
S
Krüger
Carola
C
Letellier
Elisabeth
E
Plaas
Christian
C
Dittgen
Tanjew
T
Kirsch
Friederike
F
Stieltjes
Bram
B
Weber
Daniela
D
Laage
Rico
R
Martin-Villalba
Ana
A
Schneider
Armin
A
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology* / Q000627:therapeutic use; D020439:Growth Cones / Q000187:drug effects / Q000502:physiology / Q000648:ultrastructure; D051379:Mice; D009414:Nerve Growth Factors / Q000494:pharmacology* / Q000627:therapeutic use; D016501:Neurites / Q000187:drug effects / Q000648:ultrastructure; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D011712:Pyramidal Tracts / Q000187:drug effects / Q000293:injuries / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000187:drug effects / Q000378:metabolism; D020127:Recovery of Function / Q000187:drug effects / Q000502:physiology; D013119:Spinal Cord Injuries / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D016896:Treatment Outcome; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology; D051020:bcl-X Protein / Q000187:drug effects / Q000378:metabolism
C494812:Bcl2l1 protein, mouse; D009414:Nerve Growth Factors; D018696:Neuroprotective Agents; D016188:Receptors, Granulocyte Colony-Stimulating Factor; D051020:bcl-X Protein; D016179:Granulocyte Colony-Stimulating Factor