The hematopoietic factor G-CSF is a neuronal ligand that counteracts programmed cell death and drives neurogenesis.
G-CSF is a potent hematopoietic factor that enhances survival and drives differentiation of myeloid lineage cells, resulting in the generation of neutrophilic granulocytes. Here, we show that G-CSF passes the intact blood-brain barrier and reduces infarct volume in 2 different rat models of acute stroke. G-CSF displays strong anti-apoptotic activity in mature neurons and activates multiple cell survival pathways. Both G-CSF and its receptor are widely expressed by neurons in the CNS, and their expression is induced by ischemia, which suggests an autocrine protective signaling mechanism. Surprisingly, the G-CSF receptor was also expressed by adult neural stem cells, and G-CSF induced neuronal differentiation in vitro. G-CSF markedly improved long-term behavioral outcome after cortical ischemia, while stimulating neural progenitor response in vivo, providing a link to functional recovery. Thus, G-CSF is an endogenous ligand in the CNS that has a dual activity beneficial both in counteracting acute neuronal degeneration and contributing to long-term plasticity after cerebral ischemia. We therefore propose G-CSF as a potential new drug for stroke and neurodegenerative diseases.
Schneider
Armin
A
Axaron Bioscience AG, Heidelberg, Germany. schneider@axaron.de
Krüger
Carola
C
Steigleder
Tobias
T
Weber
Daniela
D
Pitzer
Claudia
C
Laage
Rico
R
Aronowski
Jaroslaw
J
Maurer
Martin H
MH
Gassler
Nikolaus
N
Mier
Walter
W
Hasselblatt
Martin
M
Kollmar
Rainer
R
Schwab
Stefan
S
Sommer
Clemens
C
Bach
Alfred
A
Kuhn
Hans-Georg
HG
Schäbitz
Wolf-Rüdiger
WR
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001812:Blood-Brain Barrier / Q000378:metabolism; D002545:Brain Ischemia / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects*; D004195:Disease Models, Animal; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage* / Q000096:biosynthesis; D042381:Granulocyte Precursor Cells / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008297:Male; D009417:Nerve Tissue / Q000378:metabolism / Q000473:pathology; D019636:Neurodegenerative Diseases / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D009504:Neutrophils / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000096:biosynthesis*; D013234:Stem Cells / Q000378:metabolism*; D020521:Stroke / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
D008024:Ligands; D016188:Receptors, Granulocyte Colony-Stimulating Factor; D016179:Granulocyte Colony-Stimulating Factor