Brain Macrophages: Close or Distant Relatives?
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RESEARCH HIGHLIGHT
Brain Macrophages: Close or Distant Relatives? Kelei Cao1 • Yaling Hu1 • Zhihua Gao1
Received: 28 April 2020 / Accepted: 3 June 2020 Ó Shanghai Institutes for Biological Sciences, CAS 2020
The concept of a mononuclear phagocyte system in which tissue-resident macrophages arise from the circulating monocytes has been dogma in immunology for more than half a century [1]. While monocytes do give rise to macrophages under certain conditions, recent studies clearly demonstrate that monocytes do not primarily contribute to most adult tissue-resident macrophage pools under the steady state [2]. Instead, the majority of adult tissue-resident macrophages are derived from erythromyeloid progenitors (EMPs) in the yolk sac that seed tissue before birth [2]. The brain governs our recognition, emotion, and behavior. Macrophages help to maintain brain homeostasis and ensure normal function. With regard to brain macrophages, microglia, the parenchymal resident macrophages, come to mind. Other than microglia, however, the brain also contains non-parenchymal border-associated macrophages (BAMs) that reside in the choroid plexus, meninges, and perivascular spaces [3]. While microglia adopt a typical ramified morphology with thin motile processes, BAMs appear to be amoeboid-like. Unlike the well-characterized origin of microglia from the yolk sac [2], the origin of BAMs had been obscure. Due to their differences in morphology and residence, microglia and BAMs were long thought to be two ontogenetically and transcriptionally distinct myeloid populations [4]. Until recently, studies demonstrated that microglia and BAMs are closely related & Zhihua Gao [email protected] 1
Department of Neurobiology and Department of Neurology of Second Affiliated Hospital, Institute of Neuroscience, NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine, Hangzhou 310058, China
as they both appear early in the embryonic brain and share common immune-related markers such as Iba1, CD11b, and the fractalkine receptor CX3CR1 [3]. Moreover, BAMs from different border areas appear to have different ontogeny and exhibit inter- and intra-border diversity with distinct self-renewal capacity at adult stages [5]. Nonetheless, whether microglia and BAMs share a common developmental program or differ in early precursors remained unclear. Combining single-cell RNA sequencing (sc-RNA seq), flow cytometric analysis, and fate mapping models, Utz et al [6] found that BAMs and microglia may arise from a common progenitor, but diverge early with two distinct subpopulations of embryonic macrophage precursors in the yolk sac and brain, suggesting clear lineage commitment and segregation in the ontogeny of microglia and BAMs at early developmental stages. To determine whether microglia and BAMs differ at embryonic stages, Utz et al. [6] first profiled the brain macrophages by sc-RNA seq at E16.5 in mice, when microglia start differentiating and expressing signature genes. The
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