In a recent paper in Cell, Wu et al. described a novel peripheral nervous system (PNS) resident myeloid cell population, which the authors named microglia-like PNS cells.

Over the past decade, there has been heightened interest in the role of immune cells in the context of the central nervous system (CNS) in health and disease.1 A major advance in understanding this interaction arose from research demonstrating that resident microglia and blood-borne macrophages within the brain have distinct origins,2 and distinct functions.3,4 Microglia, the resident immune cells of the CNS, are derived from the myeloid lineage, and originate from the yolk sac during early developmental stages.2,5 Following this initial homing, their population is maintained through self-renewal rather than via newly migrating blood-derived monocytes that differentiate into macrophages. However, under pathological conditions in the CNS, microglia often become exhausted or even senescent,6,7 and monocyte-derived macrophages are needed for support.4

Previous studies in rodents led to the belief that resident microglia-like cells were absent from the peripheral nervous system (PNS). Yet, self-renewal of resident macrophages was reported in peripheral nerves.8 The recent study by Wu et al. reveals the presence of myeloid cells reminiscent of microglia in the dorsal root ganglia (DRG) of higher species, including humans, monkeys, and pigs, though not in rodents.9 These cells express characteristic markers of microglia, namely P2YR12 and SALL1. The microglia-like cells in the PNS are predominantly found in the pre-soma regions of these neurons. Analysis using TAC-seq and ChIP-seq demonstrated that PNS microglia-like cells share a closer similarity to microglia than to border-associated macrophages. The study reveals similar signatures and epigenetic profiles between microglia and PNS-like microglial cells, suggesting analogous ontogeny and differentiation pathways.10 Time-resolved single-cell RNA sequencing of hematopoietic cells from the human yolk sac, embryo, head, spinal cord, and DRG at different developmental stages indicates that their abundance correlates with the size of the soma.

The presence of PNS microglia-like cells, in contrast to CNS microglia,11 is not determined by evolutionary lineage alone. The exact molecular mechanisms behind this relationship in the PNS remain to be further investigated. The description of a PNS counterpart to microglia, together with the demonstration that these cells originate from the yolk sac, similar to brain microglia, emphasize the need for caution when studying small animal models. Identification of this novel population may open new avenues of research into PNS pathologies that have not been previously considered.