Abstract
Background and PurposeMicroglia are resident immunocompenent and phagocytic cells of central nervous system (CNS), which produce various cytokines and growth factors in response to injury and thereby regulate disease pathology. The purpose of this study is to investigate the effects of microglial transplantation on focal cerebral ischemia model in rat.MethodsTransient middle cerebral artery occlusion (MCAO) in rats was induced by the intraluminal filament technique. HMO6 cells, human microglial cell line, were transplanted intravenously at 48 hours after MCAO. Functional tests were performed and the infarct volume was measured at 7 and 14 days after MCAO. Migration and cell survival of transplanted microglial cells and host glial reaction in the brain were studied by immunohistochemistry. Gene expression of neurotrophic factors, cytokines and chemokines in transplanted cells and host rat glial cells was determined by laser capture microdissection (LCM) and quantitative real time-PCR.ResultsHMO6 human microglial cells transplantion group demonstrated significant functional recovery compared with control group. At 7 and 14 days after MCAO, infarct volume was significantly reduced in the HMO group. In the HMO6 group, number of apoptotic cells was time-dependently reduced in the infarct core and penumbra. In addition, number of host rat microglia/macrophages and reactive astrocytes was significantly decreased at 7 and 14 days after MCAO in the penumbra. Gene expression of various neurotrophic factors (GDNF, BDNF, VEGF and BMP7) and anti-inflammatory cytokines (IL4 and IL5) was up-regulated in transplanted HMO6 cells of brain tissue compared with those in culture. The expression of GDNF and VEGF in astrocytes in penumbra was significantly up-regulated in the HMO6 group.ConclusionsOur results indicate that transplantation of HMO6 human microglial cells reduces ischemic deficits and apoptotic events in stroke animals. The results were mediated by modulation of gliosis and neuroinflammation, and neuroprotection provided by neurotrophic factors of endogenous and transplanted cells-origin.
Highlights
Microglia are immunocompetent cells of central nervous system (CNS), which are activated in response to injury and diseases, and adopt a phagocytic and cytokine secreting phenotype [1,2,3,4]
Microglia are activated following in cerebral ischemia and express a variety of proinflammatory cytokines including interleukin -1b (IL-1b), interleukin -6 (IL-6) and tumor necrosis factor -a (TNF-a), which induce in neuroinflammation and neurotoxicity [5,6,7,8]
Neurological functional recovery We investigated whether transplanted human microglial cell, HMO6 improves neurological deficits after middle cerebral artery occlusion (MCAO) in rat
Summary
Microglia are immunocompetent cells of central nervous system (CNS), which are activated in response to injury and diseases, and adopt a phagocytic and cytokine secreting phenotype [1,2,3,4]. Microglia are activated following in cerebral ischemia and express a variety of proinflammatory cytokines including interleukin -1b (IL-1b), interleukin -6 (IL-6) and tumor necrosis factor -a (TNF-a), which induce in neuroinflammation and neurotoxicity [5,6,7,8]. Microglia is known to produce neurotrophic factors such as glial cell line-derived neurotrophic factor (GDNF), brainderived neurotrophic factor (BDNF), basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF), potentially provide trophic support to neurons in distress [12,13,14] These reports suggest that the phenotypic expression of microglia, whether it is to be neuroprotective or neurodegenerative, depends on the cue it receives during a particular disease process. The purpose of this study is to investigate the effects of microglial transplantation on focal cerebral ischemia model in rat
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