Harmonized cross-species cell atlases of trigeminal and dorsal root ganglia

Abstract

Peripheral sensory neurons in the dorsal root ganglion (DRG) and trigeminal ganglion (TG) are specialized to detect and transduce diverse environmental stimuli including touch, temperature, and pain to the central nervous system. Recent advances in single-cell RNA-sequencing (scRNA-seq) have provided new insights into the diversity of sensory ganglia cell types in rodents, non-human primates, and humans, but it remains difficult to compare transcriptomically defined cell types across studies and species. Here, we built cross-species harmonized atlases of DRG and TG cell types that describe 18 neuronal and 11 non-neuronal cell types across 6 species and 19 studies. We then demonstrate the utility of this harmonized reference atlas by using it to annotate newly profiled DRG nuclei/cells from both human and the highly regenerative axolotl. We observe that the transcriptomic profiles of sensory neuron subtypes are broadly similar across vertebrates, but the expression of functionally important neuropeptides and channels can vary notably. The new resources and data presented here can guide future studies in comparative transcriptomics, simplify cell type nomenclature differences across studies, and help prioritize targets for future pain therapy development.

RNA isoform expression landscape of the human dorsal root ganglion (DRG) generated from long read sequencing

“…Furthermore, bulk sequencing of DRGs recovered from patients with pain have revealed how changes in gene expression may drive clinical phenotypes and how these underlying drivers differ in men and women (North et al, 2019; Ray et al, 2022). Spatial and single-cell technologies have given remarkable insight into the molecular makeup of human DRG (hDRG) neurons and other cell types in the DRG, revealing unique aspects of cell types and cellular makeup of the hDRG (Bhuiyan et al, 2023; Nguyen et al, 2021; Tavares-Ferreira et al, 2022; Yu et al, 2023). A major area that is still lacking is a careful examination of hDRG isoform expression.…”

Synovial fibroblast gene expression is associated with sensory nerve growth and pain in rheumatoid arthritis

“…Laminins are large glycoproteins that are abundant in synovium, and it is possible that a compliant extracellular matrix facilitates CGRP + axon sprouting or branching. NTN4 also binds cell surface receptors, such as neogenin (42), which are expressed by human nociceptors (21,22). Avenues for future research include in vivo animal studies to test the function of NTN4, as well as other pain-associated genes, and exploration of their potential as therapeutic targets.…”

“…We repeated this receptor-ligand interaction analysis using a bulk hDRG spatial RNA-seq dataset with neuronal expression confirmed in independently generated human snRNA-seq dataset, offering increased depth of coverage and a larger number of human samples from organ donors of both sexes (21)(22)(23) and a mouse DRG scRNA-seq dataset (24). From the 815 GbGMI fibroblast painassociated genes, 158 unique ligand-receptor interactions were identified with receptors present on hDRG neurons (data file S3).…”

Interaction of human keratinocytes and nerve fiber terminals at the neuro-cutaneous unit

“…It is applicable for clinical frozen skin sections, for virtually all markers with validated antibodies, and is also applicable in large experimental groups. Intriguingly, new markers for nociceptor sub-classification are emerging via transcriptomic profiling of human DRG neurons, which will enable profiling keratinocyte-IENF interactions based on fiber subtypes ( Bhuiyan et al, 2023 ).…”