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.
Tumor-associated macrophages (TAM) are exposed to multiple microenvironmental cues in tumors, which collaborate to endow these cells with protumoral activities. Hypoxia, caused by an imbalance in oxygen supply and demand because of a poorly organized vasculature, is often a prominent feature in solid tumors.
Glioblastomas are aggressive primary brain cancers that recur as therapy-resistant tumors. Myeloid cells control glioblastoma malignancy, but their dynamics during disease progression remain poorly understood. Here, we employed single-cell RNA sequencing and CITE-Seq to map the glioblastoma immune landscape in newly diagnosed and recurrent patients and in mouse tumors. This revealed a large and diverse myeloid compartment, with dendritic cell and macrophage populations that were conserved across species and were dynamic across disease stages. Tumor-associated macrophages (TAMs) consisted of microglia-or monocyte-derived populations, with both exhibiting additional heterogeneity, including subsets with conserved lipid and hypoxic signatures. Microglia-and monocytederived TAMs (Mo-TAMs) were self-renewing populations that competed for space and could be depleted via CSF1R blockade. Microglia-derived TAMs were predominant in newly diagnosed tumors but were outnumbered by Mo-TAMs upon recurrence, especially in hypoxic tumor environments. Our results unravel the glioblastoma myeloid landscape and provide a framework for future therapeutic interventions.
Tumor-associated macrophages (TAM) are an important component of the tumor stroma and exert several tumor-promoting activities. Strongly pro-angiogenic TAMs that reside in hypoxic tumor areas highly express macrophage mannose receptor (MMR, CD206)
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