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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Figure 2

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The G-CSF receptor (A–D) and its ligand (E–I) are expressed by neurons i...
The G-CSF receptor (A–D) and its ligand (E–I) are expressed by neurons in a variety of brain regions in the rat. Among other areas, expression of the receptor was detected in pyramidal cells in cortical layer V (A); Purkinje cells in the cerebellum (B); and cerebellar nuclei (C). Importantly, this neuronal staining pattern could also be detected in the human brain (frontal cortex, D). G-CSF is expressed by neurons in many areas of the CNS. Immunohistochemistry identifies G-CSF–positive cells in the CA3 region of the hippocampus (E) and the subgranular zone and hilus of the dentate gyrus (E, arrows), the entorhinal cortex (F), the olfactory bulb (G), and cerebellar nuclei (H). Expression was also seen in cells in the SVZ (I).