Microglia, specialized immune cells of the central nervous system (CNS), have long been recognized for their ability to preserve brain homeostasis and respond to pathological disturbances [1]. These cells exhibit unique transcriptional signatures shaped by their yolk-sac (YS) origins and finely tuned by CNS-specific environmental cues [2,3,4]. To date, these specialized macrophages are thought to be exclusive to the CNS. A recent study by Wu et al., however, challenges the status quo, uncovering microglia-like cells outside the CNS and shedding light on their role in modulating neuronal soma size within the peripheral nervous system (PNS) [5].

Using single-cell RNA sequencing (scRNA-seq), Wu et al. systematically profiled immune cells in the CNS and PNS across multiple species. Through this comprehensive analysis, they identified a unique PNS macrophage population transcriptionally similar to microglia, termed PNS microglia-like cells, which are present in humans, macaques, and pigs but are absent in rodents. PNS microglia-like cells express canonical microglial markers such as P2RY12 (purinergic receptor P2Y12), TMEM119 (transmembrane protein 119), and the microglia lineage-determining transcription factor SALL1 (spalt-like transcription factor 1) but lack markers for border-associated macrophages such as MRC1 (mannose receptor C type 1) and F13A1 (coagulation factor XIII A chain). Furthermore, PNS microglia-like cells also share similar epigenetic profiles and potentially the same ontogeny as microglia. Developmentally, microglial ontogeny has been extensively studied in mouse models via lineage tracing techniques [6, 7]. To investigate the developmental trajectory of PNS microglia-like cells, Wu et al. created a time-resolved scRNA-seq dataset encompassing the human CNS and PNS tissues from CS10 (Carnegie Stage 10) to 24 PCW (postconceptional weeks) and performed trajectory analysis to infer the development of PNS microglia-like cells. These results suggest that PNS microglia-like cells are likely derived from YS macrophage progenitors and differentiate in parallel with CNS microglia.