Increasing evidence suggests that macrophages critically shape brain homeostasis and disease.However, while the pivotal role of parenchymal microglia has gradually emerged, other brain-resident myeloid cells remain elusive. By dissecting border regions and combining single-cell RNA sequencing with high-dimensional cytometry, bulk RNA-sequencing, fate-mapping and microscopy, we reveal the remarkable diversity of non-parenchymal brain macrophages. Border-associated macrophages or BAMs residing in the dura mater, subdural meninges and choroid plexus consisted of distinct subsets that exhibited tissue-specific transcriptional signatures and underwent strong compositional changes during postnatal development. The gene regulatory networks of BAMs were identified and fundamentally differed from those of microglia. Importantly, we identified a unique non-homeostatic microglia-like population residing on the apical surface of the choroid plexus epithelium. Niche accessibility drove BAM ontogeny and determined whether embryonic macrophages were progressively replaced by bone marrow progenitors. Together, our work provides important insights into the biology of brain macrophages and offers a solid framework for future investigations.
Self-renewing tissue-resident macrophages are thought to be exclusively derived from embryonic progenitors. However, whether circulating monocytes can also give rise to such macrophages has not been formally investigated. Here we use a new model of diphtheria toxin-mediated depletion of liver-resident Kupffer cells to generate niche availability and show that circulating monocytes engraft in the liver, gradually adopt the transcriptional profile of their depleted counterparts and become long-lived self-renewing cells. Underlining the physiological relevance of our findings, circulating monocytes also contribute to the expanding pool of macrophages in the liver shortly after birth, when macrophage niches become available during normal organ growth. Thus, like embryonic precursors, monocytes can and do give rise to self-renewing tissue-resident macrophages if the niche is available to them.
Highlights d Spatial proteogenomic single-cell atlas of healthy and obese murine and human liver d Validated flow cytometry and microscopy panels for all hepatic cells d LAMs are differentially located in the lean and obese liver d Evolutionary conserved BMP9/10-ALK1 axis is essential for KC development
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