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.
Highlights
Microglia represent the largest population of immune cells in the brain, constituting 5–10% of brain cells in the adult central nervous system (CNS)
Sustained high dose of colony-stimulating factor 1 receptor (CSF1R) inhibitor unmasks a distinct form of myeloid cell CNS repopulation
We have shown that 7 day treatment of the brain penetrant CSF1R/KIT/FLT3 inhibitor PLX3397 (Pexidartinib; 600 ppm in chow) eliminates ~90–98% of microglia in the CNS (Elmore et al, 2014; Najafi et al, 2018)
Summary
Microglia represent the largest population of immune cells in the brain, constituting 5–10% of brain cells in the adult central nervous system (CNS). Microglia arise from yolk sac-derived erythromyeloid progenitors and colonize the brain as embryonic microglia during early stages of development (i.e. E8.5 – E9.5) (Ginhoux et al, 2010; Kierdorf et al, 2013) These immature myeloid cells, displaying amoeboid morphology and high proliferative potential, enter the brain via the meninges and ventricles in mice (Lelli et al, 2013; Ueno et al, 2013; Swinnen et al, 2013; Xavier et al, 2015), as well as, via the leptomeninges, choroid plexus, and ventricular zone in humans (Tay et al, 2017; Verney et al, 2010; Monier et al, 2007; Ginhoux et al, 2013). We have optimized a colony-stimulating factor 1 receptor (CSF1R) inhibitor approach that involves sustained inhibitor administration, building on our prior work that microglia are dependent on this signaling for their survival (Elmore et al, 2014) This approach results in a delayed repopulation of myeloid cells that reconstitute the brain in a sequential manner previously unseen in the adult brain. These data highlight the utility of CSF1R inhibitors in identifying and studying myeloid cell homeostasis and dynamics
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