Abstract
A key concern in early-stage analgesic discovery efforts is the extent to which mechanisms identified in rodents will translate to humans. To evaluate an alternative approach to the use of rodent dissociated DRG neurons for in vitro analyses of nociceptive signaling, we performed a transcriptomic analysis of the HD10.6 human dorsal root ganglion (DRG)-derived immortalized cell line. We conducted RNA-seq on proliferating and mature HD10.6 cells to characterize transcriptional changes associated with maturation. We then compared the transcriptomes of HD10.6 cells and several recently developed lines of human induced pluripotent stem cell-derived sensory neurons (iPSC-SN) to single-nucleus RNA-seq data from human DRGs. HD10.6 cells showed the highest correlation with 3 human sensory neuron subtypes associated with nociception and pruriception. Each of the iPSC-SN lines evaluated showed a distinct pattern of correlation with human sensory neuron subtypes. We identified G protein-coupled receptors (GPCRs) and ion channels that are expressed in both HD10.6 cells and human DRG neurons, as well as numerous genes that are expressed in human DRG but not in rodent, underscoring the need for human sensory neuron in vitro models. Proof-of-concept evaluations of protein kinase A, protein kinase C and Erk signaling provide examples of scalable assays using HD10.6 cells to investigate well-established GPCR signaling pathways. We conclude that HD10.6 cells provide a versatile model for exploring human neuronal signaling mechanisms.