Single-Cell Analysis of Dorsal Root Ganglia Reveals Metalloproteinase Signaling in Satellite Glial Cells and Pain

Somatosensory stimuli such as touch, temperature and pain are transduced in the periphery and transmitted to the central nervous system by primary sensory neurons, which cell bodies reside in sensory ganglia such as dorsal root ganglia (DRGs). Although DRG are complex tissues with neuronal and non-neuronal cells, diversity of non-neuronal cells and their function in homeostasis and pain are still unclear. Satellite glial cells (SGCs) are among the most abundant non-neuronal cells in DRGs and tightly envelop neurons providing metabolic and trophic support, buffering extracellular ions and neurotransmitters, and enabling neuromodulation. Importantly, it is now clear that SGCs can control neuroinflammation and neuronal excitability contributing to development of pathological pain. Yet our understanding of SGC biology and molecular signaling is still rudimentary. Here, we used single-cell RNA sequencing (scRNA-seq) to study the heterogeneity of non-neuronal cell populations in DRGs and, in particular, to understand SGC biology and molecular signaling in the context of modulation of somatosensory stimuli and pathological pain. We identified a distinct gene expression for non-neuronal cells and heterogeneity of SGCs. In particular, we found an enriched expression of the tissue inhibitor metalloproteinase 3 (TIMP3) and other metalloproteinases in SGCs, and demonstrated using small interfering RNA and neutralizing antibody that TIMP3 controls somatosensory stimuli. TIMP3 expression is decrease after paclitaxel, and its rescue by delivery of a recombinant TIMP3 protein reversed and prevented paclitaxel-induced pain. We also established that paclitaxel directly modulates metalloproteinase signaling in cultured SGCs, which can be used to screen novel drugs for pain. Thus, our findings reveal a metalloproteinase signaling in SGCs for the proper processing of somatosensory stimuli and discovery of new treatment of pain. Grant support from NS113243.