Schneider, A, Krüger, C, Steigleder, T, Weber, D, Pitzer, C, Laage, R et al.. The hematopoietic factor G-CSF is a neuronal ligand that counteracts programmed cell death and drives neurogenesis. J Clin Invest 115: 2083-2098

Axaron Bioscience AG, Heidelberg, Germany.
Journal of Clinical Investigation (Impact Factor: 13.22). 09/2005; 115(8):2083-98. DOI: 10.1172/JCI23559
Source: PubMed


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.

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    • "Furthermore, the application of G-CSF is known to result in the mobilization of HSCs to the peripheral blood. Trafficking of HSCs to the injured neurons mediated by stromal cell-derived factor 1а has been reported to lead to the production of trophic factors that contribute to anti-inflammation, survival of the damaged neural tissue (Majka et al., 2001; Tsai et al., 2008), and neurogenesis (Shyu et al., 2004; Schneider et al., 2005). Our recent work shows that the protective actions of G-CSF in rAION models may involve both anti-apoptotic and anti-inflammatory processes. "
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    ABSTRACT: Non-arteritic anterior ischemic optic neuropathy (NA-AION) is the most common cause of acute ischemic damage to the optic nerve (ON), and the leading cause of seriously impaired vision in people over 55 years of age. It demonstrated that subcutaneous administration of Granulocyte colony-stimulating factor (G-CSF) reduces RGC death in an ON crush model in rats, and that the neuroprotective effects may involve both anti-apoptotic and anti-inflammatory processes. Our recent work shows that the protective actions of G-CSF in rAION models may involve both anti-apoptotic and anti-inflammatory processes. However, the exact rescuing mechanisms involved in the administration of G-CSF in rAION models need further investigation. In addition, further studies on the administration of G-CSF at different time intervals after the induction of rAION may be able to illustrate whether treatment given at a later time is still neuroprotective. Further, it is unknown whether treatment using G-CSF combined with other drugs will result in a synergistic effect in a rAION model. Inflammation induced by ischemia plays an essential role on the ON head in NA-AION, which can result in disc edema and compartment changes. Therefore, it is reasonable that adding an anti-inflammatory drug may enhance the therapeutic effects of G-CSF. An ongoing goal is to evaluate the novel sites of action of both G-CSF and other anti-inflammatory drugs, and to identify the functionally protective pathways to enhance RGC survival. These investigations may open up new therapeutic avenues for the treatment of ischemic optic neuropathy.
    Full-text · Article · Aug 2014 · Neural Regeneration Research
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    • "Administration of G-CSF, alone or in combination with stem cell factor, promotes cerebral angiogenesis and enhances recovery from sensory/motor deficits following ischemic cerebral lesions (Kawada et al., 2006; Lu and Xiao, 2007). In addition to its infarct-reducing effects, G-CSF enhances recovery of cognitive functions and increases hippocampal neurogenesis (Schneider et al., 2005b; Schabitz and Schneider, 2007). Finally, G-CSF is an immunomodulator and has been shown to reduce the release of proinflammatory cytokines (Hartung, 1998). "
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    ABSTRACT: Granulocyte colony-stimulating factor (G-CSF) is a hematopoietic cytokine that also possesses neurotrophic and antiapoptotic properties. G-CSF has been reported to decrease amyloid burden significantly, promote hippocampal neurogenesis, and improve spatial learning in a mouse model of Alzheimer's disease. To understand better the effects of G-CSF on hippocampal-dependent learning, the present study focused on electrophysiological correlates of neuroplasticity, long-term potentiation (LTP), and long-term depression (LTD). Two cohorts of transgenic APP/PS1 mice, with or without prior bone marrow transplantation from Tg GFP mice, were treated in vivo for 2 weeks with G-CSF or vehicle. After completion of the treatments, hippocampal slices were prepared for electrophysiological studies of LTP and LTD. LTP was induced and maintained in both G-CSF-treated and vehicle-treated groups of Tg APP/PS1. In contrast, LTD could not be induced in vehicle-treated Tg APP/PS1 mice, but G-CSF treatment restored LTD. The LTP and LTD results obtained from the cohort of bone marrow-grafted Tg APP/PS1 mice did not differ from those from nongrafted Tg APP/PS1 mice. The mechanism by which G-CSF restores LTD is not known, but it is possible that its capacity to reduce amyloid plaques results in increased soluble oligomers of amyloid-β (A-β), which in turn may facilitate LTD. This mechanism would be consistent with the recent report that soluble A-β oligomers promote LTD in hippocampal slices. © 2014 Wiley Periodicals, Inc.
    Full-text · Article · Aug 2014 · Journal of Neuroscience Research
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    • "Granulocyte-colony stimulating factor (G-CSF) is a major growth factor in the differentiation and proliferation of neutrophilic-granulocytic lineage cells that modulates the immune response by inhibiting the production of inflammatory cytokines [5], [6]. Both G-CSF and its receptor G-CSFR are widely expressed in neurons in the central nervous systems (CNS), and their expression is induced by ischemia [7]. G-CSFR is also reportedly expressed in adult neural stem cells, and G-CSF can induce neuronal differentiation in vitro [7]. "
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    ABSTRACT: Soluble oligomeric amyloid β (oAβ) causes synaptic dysfunction and neuronal cell death, which are involved in the pathogenesis of Alzheimer's disease (AD). The hematopoietic growth factor granulocyte-colony stimulating factor (G-CSF) is expressed in the central nervous system (CNS) and drives neurogenesis. Here we show that G-CSF attenuated oAβ neurotoxicity through the enhancement of the enzymatic activity of Aβ-degrading enzyme neprilysin (NEP) in neurons, while the NEP inhibitor thiorphan abolished the neuroprotection. Inhibition of MEK5/ERK5, a major downstream effector of G-CSF signaling, also ablated neuroprotective effect of G-CSF. Furthermore, intracerebroventricular administration of G-CSF enhanced NEP enzymatic activity and clearance of Aβ in APP/PS1 transgenic mice. Thus, we propose that G-CSF may be a possible therapeutic strategy against AD.
    Full-text · Article · Jul 2014 · PLoS ONE
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