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 increases neurogenesis in the dentate gyrus. (A) Example of BrdU/N...
G-CSF increases neurogenesis in the dentate gyrus. (A) Example of BrdU/NeuN-double-positive cells within the basal layer of the dentate gyrus (scale bar: 40 &____m). The arrow in A indicates the enlarged double-stained cell in B (scale bar: 10 &____m). (C) DCX in red. (D) BrdU in green. (E) NeuN in blue. (F) G-CSF increased the number of newly generated neurons (BrdU+/NeuN+) on the side of the ischemic lesion (red bars, ipsilateral + vehicle vs. ipsilateral + G-CSF; **P < 0.01). Contralateral to the lesion, there was a trend toward an increase in newly generated neurons compared with vehicle-treated ischemic animals that was not statistically significant (blue bars, contralateral + vehicle vs. contralateral + G-CSF). However, G-CSF increased neurogenesis in sham-operated, nonischemic animals (green bars, sham + vehicle vs. sham + G-CSF; *P < 0.05). (G) The total number of BrdU+ cells in the dentate gyrus was not significantly further increased by G-CSF treatment in the ischemic animals (red and blue bars), which implies a true induction of neuronal differentiation by G-CSF in the postischemic brain. In contrast, sham-lesioned animals showed an elevation of the total number of BrdU+ cells after G-CSF treatment (green bars; *P < 0.05).