Dorsal root ganglia (DRG) sensory neurons can transmit information about noxious stimulus to cerebral cortex via spinal cord, and play an important role in the pain pathway. Alterations of the pain pathway lead to CIPA (congenital insensitivity to pain with anhidrosis) or chronic pain. Accumulating evidence demonstrates that nerve damage leads to the regeneration of neurons in DRG, which may contribute to pain modulation in feedback. Therefore, exploring the regeneration process of DRG neurons would provide a new understanding to the persistent pathological stimulation and contribute to reshape the somatosensory function. It has been reported that a subpopulation of satellite glial cells (SGCs) express Nestin and p75, and could differentiate into glial cells and neurons, suggesting that SGCs may have differentiation plasticity. Our results in the present study show that DRG-derived SGCs (DRG-SGCs) highly express neural crest cell markers Nestin, Sox2, Sox10, and p75, and differentiate into nociceptive sensory neurons in the presence of histone deacetylase inhibitor VPA, Wnt pathway activator CHIR99021, Notch pathway inhibitor RO4929097, and FGF pathway inhibitor SU5402. The nociceptive sensory neurons express multiple functionally-related genes (SCN9A, SCN10A, SP, Trpv1, and TrpA1) and are able to generate action potentials and voltage-gated Na⁺ currents. Moreover, we found that these cells exhibited rapid calcium transients in response to capsaicin through binding to the Trpv1 vanilloid receptor, confirming that the DRG-SGC-derived cells are nociceptive sensory neurons. Further, we show that Wnt signaling promotes the differentiation of DRG-SGCs into nociceptive sensory neurons by regulating the expression of specific transcription factor Runx1, while Notch and FGF signaling pathways are involved in the expression of SCN9A. These results demonstrate that DRG-SGCs have stem cell characteristics and can efficiently differentiate into functional nociceptive sensory neurons, shedding light on the clinical treatment of sensory neuron-related diseases.

Graphical Abstract