Mapping Satellite Glial Cell Heterogeneity Reveals Distinct Spatial Organization and Implies Functional Diversity in the Dorsal Root Ganglion

Abstract Satellite glial cells (SGCs) enclose sensory neuron somata and initial axon segments in the dorsal root ganglia (DRG) and play a critical role in regulating the neuronal microenvironment. While DRG neuron diversity is well established, SGC heterogeneity remains poorly defined. Here, the first comprehensive in situ characterization of SGC heterogeneity within the mouse DRG is presented. By integrating single‐cell RNA sequencing with immunohistochemistry, in situ hybridization, and advanced imaging techniques, four distinct SGC subtypes are identified, validated, and spatially mapped within their native anatomical context: 1) The predominant perisomatic sheaths are defined by marker proteins traditionally used to characterize the entire SGC population, including FABP7, KIR4.1, GS, and CX43. 2) OCT6 + SGCs are occasionally found in mosaic perisomatic sheaths, and commonly ensheathing initial axon segments. 3) SCN7A + SGCs lacking traditional markers and forming specialized sheaths around nonpeptidergic neurons, suggesting a role in itch signaling. 4) Interferon response gene‐expressing SGCs, responding to Herpes Simplex Virus, suggesting potential involvement in antiviral protection. Finally, human DRG is investigated and distinct inner and outer perisomatic layers with differential expression of markers are observed. The results provide novel insight into SGC heterogeneity, suggesting distinct functional properties for such subtypes of relevance for the neuronal microenvironment.