The hematopoietic factor G-CSF is a neuronal ligand that counteracts programmed cell death and drives neurogenesis
Armin Schneider, … , Hans-Georg Kuhn, Wolf-Rüdiger Schäbitz
Armin Schneider, … , Hans-Georg Kuhn, Wolf-Rüdiger Schäbitz
Published August 1, 2005
Citation Information: J Clin Invest. 2005;115(8):2083-2098. https://doi.org/10.1172/JCI23559.
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Research Article Neuroscience

The hematopoietic factor G-CSF is a neuronal ligand that counteracts programmed cell death and drives neurogenesis

Abstract

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 antiapoptotic 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.

Authors

Armin Schneider, Carola Krüger, Tobias Steigleder, Daniela Weber, Claudia Pitzer, Rico Laage, Jaroslaw Aronowski, Martin H. Maurer, Nikolaus Gassler, Walter Mier, Martin Hasselblatt, Rainer Kollmar, Stefan Schwab, Clemens Sommer, Alfred Bach, Hans-Georg Kuhn, Wolf-Rüdiger Schäbitz

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G-CSF and its receptor are induced by cerebral ischemia. (A–C) Quantitat...
G-CSF and its receptor are induced by cerebral ischemia. (A–C) Quantitative PCR demonstrates induction of mRNA following cerebral ischemia. (A) In the MCAO model, G-CSF mRNA is induced more than 100-fold in the ipsilateral and contralateral forebrain hemisphere at 2 hours following ischemia. At 6 hours, induction levels dropped, and overexpression became more specific to the ipsilateral hemisphere. At 20 hours, induction was no longer detectable (data not shown). (B) Moderate induction of the G-CSF receptor mRNA in forebrain hemispheres was seen 6 hours following MCAO. (C) Receptor induction was also detected 6 hours after ischemia in another ischemic model, cortical photothrombotic ischemia in biopsy material from the periinfarct cortex. The substantially higher induction reflects the strong induction in the infarct penumbral zone. (D–O) Immunohistochemical detection of receptor and ligand in the corresponding ischemia models. (D–I) Staining for G-CSF receptor (D–F) and ligand (G–I) in the MCAO model, 6 hours after ischemia: ipsilateral cortex (D and G) and corresponding areas of the contralateral hemisphere (E and H) and the cortex of a sham-operated rat (F and I). (J–O) Staining for G-CSF receptor (J–L) and G-CSF itself (M–O) in the photothrombotic model: ipsilateral cortex (J and M) and corresponding areas of the contralateral hemisphere (K and N) and the cortex of a sham-operated rat (L and O). The infarct border zone is shown in the upper-right quadrant in D, G, J, and M and is particularly clear in the photothrombotic model. Note the strong dendritic staining for the G-CSFR. Original magnification ×20.