TY - JOUR
T1 - Systemic G-CSF attenuates cerebral inflammation and hypomyelination but does not reduce seizure burden in preterm sheep exposed to global hypoxia-ischemia
AU - Jellema, Reint K.
AU - Lima Passos, Valéria
AU - Ophelders, Daan R.M.G.
AU - Wolfs, Tim G.A.M.
AU - Zwanenburg, Alex
AU - De Munter, Stephanie
AU - Nikiforou, Maria
AU - Collins, Jennifer J.P.
AU - Kuypers, Elke
AU - Bos, Gerard M.J.
AU - Steinbusch, Harry W.
AU - Vanderlocht, Joris
AU - Andriessen, Peter
AU - Germeraad, Wilfred T.V.
AU - Kramer, Boris W.
N1 - © 2013.
PY - 2013/12/1
Y1 - 2013/12/1
N2 - 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 (100. μg/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.
AB - 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 (100. μg/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.
KW - Animals
KW - Disease Models, Animal
KW - Electrocardiography
KW - Electroencephalography
KW - Encephalitis/etiology
KW - Fetal Hypoxia/complications
KW - Fetus
KW - Flow Cytometry
KW - Granulocyte Colony-Stimulating Factor/pharmacology
KW - Hematopoietic Stem Cell Mobilization
KW - Hypoxia-Ischemia, Brain/complications
KW - Immunohistochemistry
KW - Nerve Fibers, Myelinated/drug effects
KW - Neuroprotective Agents/pharmacology
KW - Seizures/etiology
KW - Sheep
UR - https://www.scopus.com/pages/publications/84886391856
U2 - 10.1016/j.expneurol.2013.09.026
DO - 10.1016/j.expneurol.2013.09.026
M3 - Article
C2 - 24120465
SN - 0014-4886
VL - 250
SP - 293
EP - 303
JO - Experimental Neurology
JF - Experimental Neurology
ER -