title: Systemic G-CSF attenuates cerebral inflammation and hypomyelination but does not reduce seizure burden in preterm sheep exposed to global hypoxia-ischemia.
abstract: Hypoxic-ischemic encephalopathy (HIE) is common in preterm infants, but currently no curative therapy is available. Cell-based therapy has a great potential in the treatment of hypoxic-ischemic preterm brain injury. Granulocyte-colony stimulating factor (G-CSF) is known to mobilize endogenous hematopoietic stem cells (HSC) and promotes proliferation of endogenous neural stem cells. On these grounds, we hypothesized that systemic G-CSF would be neuroprotective in a large translational animal model of hypoxic-ischemic injury in the preterm brain. Global hypoxia-ischemia (HI) was induced by transient umbilical cord occlusion in instrumented preterm sheep. G-CSF treatment (100μg/kg intravenously, during five consecutive days) was started one day before the global HI insult to ascertain mobilization of endogenous stem cells within the acute phase after global HI. Mobilization of HSC and neutrophils was studied by flow cytometry. Brain sections were stained for microglia (IBA-1), myelin basic protein (MBP) and myeloperoxidase (MPO) to study microglial proliferation, white matter injury and neutrophil invasion respectively. Electrographic seizure activity was analyzed using amplitude-integrated electroencephalogram (aEEG). G-CSF effectively mobilized CD34-positive HSC in the preterm sheep. In addition, G-CSF caused marked mobilization of neutrophils, but did not influence enhanced invasion of neutrophils into the preterm brain after global HI. Microglial proliferation and hypomyelination following global HI were reduced as a result of G-CSF treatment. G-CSF did not cause a reduction of the electrographic seizure activity after global HI. In conclusion, G-CSF induced mobilization of endogenous stem cells which was associated with modulation of the cerebral inflammatory response and reduced white matter injury in an ovine model of preterm brain injury after global HI. G-CSF treatment did not improve neuronal function as shown by seizure analysis. Our study shows that G-CSF treatment has neuroprotective potential following hypoxic-ischemic injury in the preterm brain.
authors.affiliation: School of Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands; Department of Pediatrics, Maastricht University Medical Center+, Maastricht, The Netherlands.
authors.forename: Reint K
authors.initials: RK
authors.lastname: Jellema
authors.forename: Valéria
authors.initials: V
authors.lastname: Lima Passos
authors.forename: Daan R M G
authors.initials: DR
authors.lastname: Ophelders
authors.forename: Tim G A M
authors.initials: TG
authors.lastname: Wolfs
authors.forename: Alex
authors.initials: A
authors.lastname: Zwanenburg
authors.forename: Stephanie
authors.initials: S
authors.lastname: De Munter
authors.forename: Maria
authors.initials: M
authors.lastname: Nikiforou
authors.forename: Jennifer J P
authors.initials: JJ
authors.lastname: Collins
authors.forename: Elke
authors.initials: E
authors.lastname: Kuypers
authors.forename: Gerard M J
authors.initials: GM
authors.lastname: Bos
authors.forename: Harry W
authors.initials: HW
authors.lastname: Steinbusch
authors.forename: Joris
authors.initials: J
authors.lastname: Vanderlocht
authors.forename: Peter
authors.initials: P
authors.lastname: Andriessen
authors.forename: Wilfred T V
authors.initials: WT
authors.lastname: Germeraad
authors.forename: Boris W
authors.initials: BW
authors.lastname: Kramer
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004562:Electrocardiography; D004569:Electroencephalography; D004660:Encephalitis / Q000209:etiology / Q000473:pathology*; D005311:Fetal Hypoxia / Q000150:complications* / Q000473:pathology; D005333:Fetus; D005434:Flow Cytometry; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology*; D019650:Hematopoietic Stem Cell Mobilization; D020925:Hypoxia-Ischemia, Brain / Q000150:complications* / Q000473:pathology; D007150:Immunohistochemistry; D009413:Nerve Fibers, Myelinated / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology*; D012640:Seizures / Q000209:etiology; D012756:Sheep
chemical_list: D018696:Neuroprotective Agents; D016179:Granulocyte Colony-Stimulating Factor
keywords: G-CSF; Hypoxic–ischemic encephalopathy; Neuroprotection; Preterm; Sheep model; Stem cells; White matter injury