Abstract
Emerging evidence suggests that microglia can support neurogenesis. Little is known about the mechanisms by which microglia regulate the cortical environment and stimulate cortical neurogenesis. We used an in vitro co-culture model system to investigate the hypothesis that microglia respond to soluble signals from cortical cells, particularly following mechanical injury, to alter the cortical environment and promote cortical cell proliferation, differentiation, and survival. Analyses of cortical cell proliferation, cell death, neurogenic protein expression, and intracellular signaling were performed on uninjured and injured cortical cells in co-culture with microglial cell lines. Microglia soluble cues enhanced cortical cell viability and proliferation cortical cells. Co-culture of injured cortical cells with microglia significantly reduced cell death of cortical cells. Microglial co-culture significantly increased Nestin + and α-internexin + cortical cells. Multiplex ELISA and RT-PCR showed decreased pro-inflammatory cytokine production by microglia co-cultured with injured cortical cells. Inhibition of AKT phosphorylation in cortical cells blocked microglial-enhanced cortical cell viability and expression of neurogenic markers in vitro. This in vitro model system allows for assessment of the effect of microglial-derived soluble signals on cortical cell viability, proliferation, and stages of differentiation during homeostasis or following mechanical injury. These data suggest that microglia cells can downregulate inflammatory cytokine production following activation by mechanical injury to enhance proliferation of new cells capable of neurogenesis via activation of AKT intracellular signaling. Increasing our understanding of the mechanisms that drive microglial-enhanced cortical neurogenesis during homeostasis and following injury in vitro will provide useful information for future primary cell and in vivo studies.
Highlights
Microglia are resident immunocompetent and phagocytic cells of the central nervous system (CNS) and comprise anywhere from 5–12% of cortical cells [45, 63]
In vitro co-cultures were established to investigate the effect of microglial soluble cues on cortical cell proliferation, survival, and differentiation during homeostasis and following cortical cell mechanical injury
1.9 ± 0.6% were immunopositive for the microglial marker CD11b (CD11b +) demonstrating that the culture conditions did not support primary microglial cell proliferation and survival (Fig. 1e)
Summary
Microglia are resident immunocompetent and phagocytic cells of the central nervous system (CNS) and comprise anywhere from 5–12% of cortical cells [45, 63]. Specific microglial-derived cytokines, growth factors, and cell associated proteins may play an important role in the modification and function of both excitatory and inhibitory synaptic connections in the CNS [11, 54, 62, 71]. Secretion of insulin growth factor 1 (IGF-1) from microglia following status epilepticus in the adult dentate gyrus stimulates neurogenesis via activation of the p42/44 MAPK pathway [84]. Other studies suggest that injury to adult CA1 neurons of the dentate gyrus stimulates IGF-1 release from microglia and astrocytes promoting neuronal survival via AKT phosphorylation and decreased MAPK phosphorylation [80] or via both AKT and MAPK phosphorylation [73]
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