Specification of CNS macrophage subsets occurs postnatally in defined niches

All tissue-resident macrophages of the central nervous system (CNS)—including parenchymal microglia, as well as CNS-associated macrophages (CAMs¹) such as meningeal and perivascular macrophages^2–7—are part of the CNS endogenous innate immune system that acts as the first line of defence during infections or trauma^2,8–10. It has been suggested that microglia and all subsets of CAMs are derived from prenatal cellular sources in the yolk sac that were defined as early erythromyeloid progenitors^11–15. However, the precise ontogenetic relationships, the underlying transcriptional programs and the molecular signals that drive the development of distinct CAM subsets in situ are poorly understood. Here we show, using fate-mapping systems, single-cell profiling and cell-specific mutants, that only meningeal macrophages and microglia share a common prenatal progenitor. By contrast, perivascular macrophages originate from perinatal meningeal macrophages only after birth in an integrin-dependent manner. The establishment of perivascular macrophages critically requires the presence of arterial vascular smooth muscle cells. Together, our data reveal a precisely timed process in distinct anatomical niches for the establishment of macrophage subsets in the CNS.