Subventricular zone/white matter microglia reconstitute the empty adult microglial niche in a dynamic wave

Abstract

Microglia, the brain's resident myeloid cells, play central roles in brain defense, homeostasis, and disease. Using a prolonged colony-stimulating factor 1 receptor inhibitor (CSF1Ri) approach, we report an unprecedented level of microglial depletion and establish a model system that achieves an empty microglial niche in the adult brain. We identify a myeloid cell that migrates from the subventricular zone and associated white matter areas. Following CSF1Ri, these amoeboid cells migrate radially and tangentially in a dynamic wave filling the brain in a distinct pattern, to replace the microglial-depleted brain. These repopulating cells are enriched in disease-associated microglia genes and exhibit similar phenotypic and transcriptional profiles to white matter-associated microglia. Our findings shed light on the overlapping and distinct functional complexity and diversity of myeloid cells of the CNS and provide new insight into repopulating microglia function and dynamics in the mouse brain.

Absence of microglia promotes diverse pathologies and early lethality in Alzheimer’s disease mice

“…Following unilateral transplantation, we observed partial microglial repopulation emanating from the injection site and the appearance of ''wavefronts'' of proliferative Ki67 + microglia adjacent to unoccupied regions of the brain (Figures 3H-3N). These wavefronts appear to be highly similar to those recently described during microglial repopulation following complete pharmacological depletion (Hohsfield et al, 2021). Thus, WT microglia appear capable of repopulating the entire brain of FIRE mice within 3 months.…”

Neuronal apoptosis drives remodeling states of microglia and shifts in survival pathway dependence

“…Here, we identify specific remodeling states of microglia that persist following CSF1R inhibition showing reduced homeostatic gene expression. Other groups recently found small populations of CSF1R-independent or repopulating microglia in the brain, and we note similar patterns of gene expression, with reduced homeostatic genes such as Tmem119 and P2ry12 , and increased expression of genes such as Lyz2 ( Zhan et al, 2020 ; Hohsfield et al, 2021 ). In these microglia repopulation studies, it was proposed that more immature microglia survive CSF1R inhibition, but microglia maturation may not be a key factor in the context of development since we previously found greater dependence of retinal microglia on CSF1R at embryonic stages ( Anderson et al, 2019b ) than in postnatal retina ( Anderson et al, 2019a ).…”

Region-Specific Characteristics of Astrocytes and Microglia: A Possible Involvement in Aging and Diseases

“…Along with the hippocampus, the SVZ is a well-known niche for adult neurogenesis [ 140 , 141 , 142 ]. Due to its specific function in the brain, recent studies showed that a particular subpopulation of microglia might be involved in SVZ-specific neurogenesis [ 53 , 143 , 144 ]. One study demonstrated that microglia with a discrete morphology, such as having an amoeboid-like form and shorter branches, mediate SVZ neurogenesis [ 143 ].…”