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Monocytes can efficiently replace all brain macrophages and instruct different microglial identities depending on their origin

ABSTRACT: Microglia and border-associated macrophages (BAMs) are critical for brain health and their dysfunction is closely linked to disease. Replacing brain macrophages holds significant therapeutic promise, but remains challenging. Here, we demonstrate that monocytes can efficienty replace all brain macrophages. Monocytes readily replaced embryonal BAMs upon their depletion and engrafted as monocyte-derived microglia (Mo-Microglia) upon more sustained niche availability. Mo-Microglia expanded comparably to their embryonic counterparts and showed similar longevity. However, monocytes were unable to replicate the unique identity of embryonically-derived BAMs and microglia. Using humanized models, we found that human monocytes exhibited similar behavior, enabling us to identify putative Mo-Microglia in Alzheimer’s disease patients. In mice and humans, the ontogeny of monocytes shaped their identity as brain macrophages. Importantly, mouse fetal liver monocytes exhibited a distinct epigenetic landscape and could develop a bonafide microglial identity. Our results illuminate brain macrophage development and highlight the potential of monocytes as an abundant progenitor source for brain macrophage replacement therapies.

ORGANISM(S): Mus musculus

PROVIDER: GSE292830 | GEO | 2025/04/22

REPOSITORIES: GEO

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Project description:Mutations in methyl-CpG-binding protein 2 (MeCP2), a major epigenetic regulator, are the predominant cause of Rett syndrome, an X-linked neurodevelopmental disorder. We previously found that Mecp2-null microglia are functionally impaired, and that engraftment of wild-type monocytes into the brain of Mecp2-deficient mice attenuates pathology. In this study we show that Mecp2 is expressed in macrophage and monocyte populations throughout the body, and is indispensable for their transcriptional regulation in multiple contexts. We demonstrate that Mecp2-null mice progressively lose or are chronically deficient in several macrophage populations and resident monocytes. Postnatal re-expression of Mecp2 driven by a tamoxifen-inducible CX3CR1 promoter significantly increased the lifespan of otherwise Mecp2-null mice, suggesting that epigenetic regulation of macrophage function by Mecp2 significantly contributes to pathology. RNA-Seq of acutely isolated microglia and peritoneal macrophages (to our knowledge, the first cell-specific RNA-Seq analysis comparing Mecp2-null and wild type cells of any kind) revealed significantly increased transcription of glucocorticoid- and hypoxia-signaling genes in Mecp2-null cells compared to that in their wild-type counterparts, suggesting that Mecp2 functions as a repressor of these pathways. Furthermore, in-vitro and in vivo validation studies demonstrated that the absence of Mecp2 is associated with cell-intrinsic dysfunction of signaling underlying inflammatory activation, suggesting that Mecp2 is important for regulation of specific macrophage gene-expression programs in response to stimuli and stressors. Our findings demonstrate a fundamental role for Mecp2 in the regulation of macrophage functions, which may provide a link to pathologies in Rett syndrome across multiple organs. Mecp2-null microglia and resident peritoneal macrophages from 10-12 week old mice were acutely isolated via AutoMACS, total RNA collected, and analyzed via RNA-Seq to compare for transcriptional differences in microglia and macrophages in the absence of Mecp2.

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Monocytes can efficiently replace all brain macrophages and instruct different microglial identities depending on their origin

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