Proximal recolonization by self-renewing microglia re-establishes microglial homeostasis in the adult mouse brain

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Abstract
Microglia are resident immune cells that play critical roles in maintaining the normal physiology of the central nervous system (CNS). Remarkably, microglia have an intrinsic capacity to repopulate themselves after acute ablation. However, the underlying mechanisms that drive such restoration remain elusive. Here, we characterized microglial repopulation both spatially and temporally following removal via treatment with the colony stimulating factor 1 receptor (CSF1R) inhibitor PLX5622. We show that microglia were replenished via self-renewal, with no contribution from nonmicroglial lineages, including Nestin+ progenitors and the circulating myeloid population. Interestingly, spatial analyses with dual-color labeling revealed that newborn microglia recolonized the parenchyma by forming distinctive clusters that maintained stable territorial boundaries over time, indicating the proximal expansive nature of adult microgliogenesis and the stability of microglia tiling. Temporal transcriptome profiling at different repopulation stages revealed that adult newborn microglia gradually regain steady-state maturity from an immature state that is reminiscent of the neonatal stage and follow a series of maturation programs, including nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation, interferon immune activation, and apoptosis. Importantly, we show that the restoration of microglial homeostatic density requires NF-κB signaling as well as apoptotic egress of excessive cells. In summary, our study reports key events that take place from microgliogenesis to homeostasis reestablishment. Microglia are the brain’s primary immune sentinels. After being seeded in the central nervous system (CNS) during embryonic development, microglia form an evenly distributed grid-like population in the adult brain. In the adult, microglia have the remarkable ability to regenerate and restore their population following acute insults, but what drives this homeostatic process is unclear. Here, we addressed this question by studying regeneration following chemical ablation of microglia. In this model, we addressed the origin of repopulating cells, their spatial redistribution characteristics, and the temporal spectrum of gene-expression patterns at different stages of repopulation. We found that the restoration of microglial homeostasis during repopulation is achieved through self-renewal, proximity clonal expansion, and activation of maturation programs.
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Funding Information
  • National Institute on Aging (R01AG051390)
  • National Institute on Aging (R01AG054214)

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