Abstract
SummaryMicroglia play key roles in brain development, homeostasis, and function, and it is widely assumed that the adult population is long lived and maintained by self-renewal. However, the precise temporal and spatial dynamics of the microglial population are unknown. We show in mice and humans that the turnover of microglia is remarkably fast, allowing the whole population to be renewed several times during a lifetime. The number of microglial cells remains steady from late postnatal stages until aging and is maintained by the spatial and temporal coupling of proliferation and apoptosis, as shown by pulse-chase studies, chronic in vivo imaging of microglia, and the use of mouse models of dysregulated apoptosis. Our results reveal that the microglial population is constantly and rapidly remodeled, expanding our understanding of its role in the maintenance of brain homeostasis.
Highlights
Microglial cells are the brain’s resident innate immune cells, with proposed key roles in brain communication and the control of inflammation in brain disease (Gomez-Nicola and Perry, 2015), the developmental control of neurogenesis (Cunningham et al, 2013), wiring (Squarzoni et al, 2014) and synaptic pruning (Paolicelli et al, 2011), the monitoring of synaptic activity (Wake et al, 2009) and the regulation of adult neurogenesis (Sierra et al, 2010)
It is unclear whether proliferation alone can account for the rapid increase in microglial numbers and suggests the possibility of additional recruitment and differentiation from blood-derived monocytes perinatally (Ginhoux et al, 2013), the contribution of monocytes has not been observed in fate mapping studies (Hoeffel et al, 2015; Sheng et al, 2015)
A Perinatal Wave of Infiltrating Monocytes Does Not Contribute to the Adult Microglial Population evidence supports the concept that the adult microglial population is generated from yolk sac emigrants (Ginhoux et al, 2010), followed by a wave of microglial proliferation (Nikodemova et al, 2015), it is unclear whether this alone accounts for the total increase in microglial cell numbers
Summary
Microglial cells are the brain’s resident innate immune cells, with proposed key roles in brain communication and the control of inflammation in brain disease (Gomez-Nicola and Perry, 2015), the developmental control of neurogenesis (Cunningham et al, 2013), wiring (Squarzoni et al, 2014) and synaptic pruning (Paolicelli et al, 2011), the monitoring of synaptic activity (Wake et al, 2009) and the regulation of adult neurogenesis (Sierra et al, 2010). Microglia are derived from the yolk sac at embryonic day (E) 8.5 (Ginhoux et al, 2010), a lineage distinct from most other tissue-resident macrophages (Hoeffel et al, 2015), and they acquire their definitive local density soon after birth, after a wave of microglial proliferation at early postnatal stages (Nikodemova et al, 2015) It is unclear whether proliferation alone can account for the rapid increase in microglial numbers and suggests the possibility of additional recruitment and differentiation from blood-derived monocytes perinatally (Ginhoux et al, 2013), the contribution of monocytes has not been observed in fate mapping studies (Hoeffel et al, 2015; Sheng et al, 2015). Microglia are rarely replaced by bone marrow (BM)-derived progenitors in health or disease (Gomez-Nicola and Perry, 2015) These observations suggest that microglia resemble the behavior of other tissueresident macrophage populations, like lung or BM macrophages, which are maintained by self-renewal in the steady state (Hashimoto et al, 2013). These studies suggest that microglia are a dynamic population and give some clues about the molecular determinants of the repopulation response, we do not know the rules governing the homeostatic maintenance of microglia during an organism’s lifetime
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