Axaron Bioscience AG

G-CSF (Granulocyte-colony stimulating factor) is a hematopoietic growth factor that has been known for 20 years, and has been named for its role in the proliferation and differentiation of cells of the myeloic lineage. We have uncovered a novel spectrum of activities of G-CSF in the central nervous system. G-CSF and its receptor are expressed by neurons in many brain regions, and are upregulated upon experimental stroke. In neurons, G-CSF acts anti-apoptotically by activating several protective pathways. In vivo, G-CSF decreases infarct volumes in acute stroke models in rodents. Moreover, G-CSF stimulates neuronal differentiation of adult neural stem cells in the brain, and improves long-term recovery in more chronic stroke models. Thus, G-CSF is a novel neurotrophic factor, and a highly attractive candidate for the treatment of neurodegenerative conditions. Here we discuss this new property of G-CSF in contrast to its known functions in the hematopoietic system, summarize data from other groups on G-CSF's actions in cerebral ischemia, compare G-CSF to Erythropoietin (EPO) in the CNS, and highlight clinical implications.

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.

Vascular endothelium forms a continuous, semipermeable barrier that regulates the transvascular movement of hormones, macromolecules, and other solutes. Here, we describe a novel immediate early gene that is expressed selectively in vascular endothelial cells,verge(vascular early response gene). Verge protein includes an N-terminal region of ∼70 amino acids with modest homology (∼30% identity) to Apolipoprotein L but is otherwise unique. Verge mRNA and protein are induced selectively in the endothelium of adult vasculature by electrical or chemical seizures. Verge expression appears to be responsive to local tissue conditions, because it is induced in the hemisphere ipsilateral to transient focal cerebral ischemia. In contrast to the transient expression in adult, Verge mRNA and protein are constitutively expressed at high levels in the endothelium of developing tissues (particularly heart) in association with angiogenesis. Verge mRNA is induced in cultured endothelial cells by defined growth factors and hypoxia. Verge protein is dramatically increased by cysteine proteinase inhibitors, suggesting rapid turnover, and is localized to focal regions near the periphery of the cells. Endothelial cell lines that stably express Verge form monolayers that show enhanced permeability in response to activation of protein kinase C by phorbol esters. This response is accompanied by reorganization of the actin cytoskeleton and the formation of paracellular gaps. These studies suggest that Verge functions as a dynamic regulator of endothelial cell signaling and vascular function.