Fate Mapping Analysis Reveals That Adult Microglia Derive from Primitive Macrophages

Department of Gene and Cell Medicine and the Immunology Institute, Mount Sinai School of Medicine, 1425 Madison Avenue, New York, NY 10029, USA.
Science (Impact Factor: 33.61). 10/2010; 330(6005):841-5. DOI: 10.1126/science.1194637
Source: PubMed


Microglia are the resident macrophages of the central nervous system and are associated with the pathogenesis of many neurodegenerative
and brain inflammatory diseases; however, the origin of adult microglia remains controversial. We show that postnatal hematopoietic
progenitors do not significantly contribute to microglia homeostasis in the adult brain. In contrast to many macrophage populations,
we show that microglia develop in mice that lack colony stimulating factor-1 (CSF-1) but are absent in CSF-1 receptor–deficient
mice. In vivo lineage tracing studies established that adult microglia derive from primitive myeloid progenitors that arise
before embryonic day 8. These results identify microglia as an ontogenically distinct population in the mononuclear phagocyte
system and have implications for the use of embryonically derived microglial progenitors for the treatment of various brain

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Available from: E. Richard Stanley
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    • "Transcript levels of three of the four genes tested (Fcrls, Itgb5, Sall1, and Tgfb1) are significantly greater in IMG cells compared to BV-2 cells (Fig. 2c). These combined data suggest that IMG cells are a pure population with both morphology and biomarkers associated with adult microglia[16]. "
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    ABSTRACT: Alzheimer’s disease is associated with amyloid-beta (Aβ)-induced microglia activation. This pro-inflammatory response promotes neuronal damage, and therapies are sought to limit microglial activation. Screening efforts to develop new pharmacological inhibitors require a robust in vitro cell system. Current models lack significant responses to Aβ, and their use in examining age-related neurodegenerative diseases is questionable. For example, the commonly used BV-2 microglial line was derived from embryonic mononuclear cells and its activation by various stimuli is limited. To this end, we have established a new immortalized microglial (IMG) cell line from adult murine brain. The objective of this study was to characterize Aβ-induced activation of IMG cells, and here, we demonstrate the ability of cannabinoids to significantly reduce this inflammatory response. Microglial cells derived from adult murine brain were immortalized via infection with the v-raf/v-myc retrovirus under conditions that selectively promote microglia growth. The presence or absence of markers CD11b and F4/80 (microglial), NeuN (neuronal), and GFAP (astrocytic) was assessed by immunofluorescence microscopy and western blotting. Using IMG and BV-2 cells, levels of pro- and anti-inflammatory transcripts in response to extracellular stimuli were determined by quantitative PCR (qPCR). Phagocytosis of fluorescent beads and fluorescein isothiocyanate (FITC)-labeled Aβ oligomers was assessed using flow cytometry and fluorescence microscopy. FITC-Aβ uptake was quantified using a fluorescence plate reader. The ability of cannabinoids to mitigate Aβ-induced expression of inducible nitric oxide synthase (iNOS) was evaluated. IMG cells express the microglial markers CD11b and F4/80 but not NeuN or GFAP. Relative to BV-2 cells, IMG cells increased iNOS (>200-fold) and Arg-1 (>100-fold) in response to pro- and anti-inflammatory stimuli. IMG cells phagocytose foreign particles and Aβ oligomers, with the latter trafficked to phagolysosomes. Aβ-induced activation of IMG cells was suppressed by delta-9-tetrahydrocannabinol and the CB2-selective agonist JWH-015 in a time- and concentration-dependent manner. IMG cells recapitulate key features of microglial cell activation. As an example of their potential pharmacological use, cannabinoids were shown to reduce activation of Aβ-induced iNOS gene expression. IMG cells hold promising potential for drug screening, mechanistic studies, and functional investigations directed towards understanding how Aβ interacts with microglia.
    Full-text · Article · Dec 2016 · Journal of Neuroinflammation
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    • "Deficiencies in microglia-mediated Ab phagocytosis have also been reported in AD[43], suggesting that microglia lose their ability to clear Ab deposits with age and disease . The similar ontology between monocytes, macrophages, and microglia[44]and the previously mentioned observations gave strength to the hypothesis that circulating monocytes could fulfill the role of microglia, providing an alternative pathway for Ab clearance[2]. However , for this process to occur efficiently, both in vascular deposition sites and the brain parenchyma, blood monocytes would have to migrate, infiltrate the brain microenvironment , and differentiate into efficient phagocytes. "
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    ABSTRACT: Mononuclear phagocytes play a critical role during Alzheimer's disease (AD) pathogenesis due to their contribution to innate immune responses and amyloid beta (Aβ) clearance mechanisms.
    Full-text · Article · Dec 2015
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    • "Meyer et al . , 2006 ) , a developmental age at which immature microglia , the resident immune cells of the brain , have not yet invaded the fetal central nervous system ( CNS ; Ginhoux et al . , 2010 ; Rigato et al . , 2011 ; Swinnen et al . , 2013 ) . Microglia colonize the brain early during embryonic development ( E11 . 5 in the mouse embryo ; Ginhoux et al . , 2010 ; Rigato et al . , 2011 ; Swinnen et al . , 2013 ) and are known to control several developmental processes in the brain at perinatal developmental stages ( Cunningham et al . , 2013 ; Squarzoni et al . , 2014 ; Michell - Robinson et al . , 2015 ) . First , embryonic microglia have been shown to be involved in angiogenesis through close"

    Full-text · Article · Dec 2015
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