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.
Highlights
Microglia are resident parenchymal macrophages in the central nervous system (CNS)
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
Summary
Microglia are resident parenchymal macrophages in the central nervous system (CNS). Along with the perivascular, meningeal, and choroid plexus macrophages, these cells govern the innate immunity of the CNS [1]. How microglia repopulate the brain following microglial ablation has been intensely debated in the field It has been shown by multiple groups that the empty microglial niche can be readily repopulated in a matter of days after ablation of more than 90% of cells using colony stimulating factor 1 receptor (CSF1R) inhibitor [8, 9]. In this setting, Elmore and colleagues described a highly proliferative Nestin+ nonmicroglial population, which preceded the appearance of microglial markers, leading to the conclusion that a hidden CNS Nestin+ progenitor pool can rapidly replenish microglia deficiency [8]. Nestin+ progenitors transitioning into adult microglia have not been detected in microglia generated under steady-state conditions [11]
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