Resilience to Pain: A Peripheral Component Identified Using Induced Pluripotent Stem Cells and Dynamic Clamp

Abstract

Pain is a complex process that involves both detection in the peripheral nervous system and perception in the CNS. Individual-toindividual differences in pain are well documented, but not well understood. Here we capitalized on inherited erythromelalgia (IEM), a well characterized human genetic model of chronic pain, and studied a unique family containing related IEM subjects with the same disease-causing Na V 1.7 mutation, which is known to make dorsal root ganglion (DRG) neurons hyperexcitable, but different pain profiles (affected son with severe pain, affected mother with moderate pain, and an unaffected father). We show, first, that, at least in some cases, relative sensitivity to pain can be modeled in subject-specific induced pluripotent stem cell (iPSC)-derived sensory neurons in vitro; second, that, in some cases, mechanisms operating in peripheral sensory neurons contribute to interindividual differences in pain; and third, using whole exome sequencing (WES) and dynamic clamp, we show that it is possible to pinpoint a specific variant of another gene, KCNQ in this particular kindred, that modulates the excitability of iPSC-derived sensory neurons in this family. While different gene variants may modulate DRG neuron excitability and thereby contribute to interindividual differences in pain in other families, this study shows that subject-specific iPSCs can be used to model interindividual differences in pain. We further provide proof-of-principle that iPSCs, WES, and dynamic clamp can be used to investigate peripheral mechanisms and pinpoint specific gene variants that modulate pain signaling and contribute to interindividual differences in pain.

Small‐fiber neuropathy: Expanding the clinical pain universe

“…Multiple modulatory factors can shape the pain experience of patients carrying Nav1.7 gain‐of‐function mutations; for example, a recent study of two patients with IEM both carrying the same Nav1.7mutation but with different pain profiles, demonstrated that a variant of a second gene, in a potassium channel, can introduce a degree of resilience to pain . Moreover, Nav1.7 mutations may affect multiple cell types including some cells outside the nervous system.…”

The Two Sides of NaV1.7: Painful and Painless Channelopathies

“…iPSC-Noc cells from both subjects were hyperexcitable. However, there was a lower level of excitability in the iPSC-Noc from the patient with pain resilience, and a GOF mutation in Kv7.2 potassium channels was found to be responsible (Mis et al, 2019). Both studies highlight the utility of iPSC-derived nociceptors for pain research.…”

“…McDermott et al (2019) used iPSC-Noc to assess the impact of Na V 1.7 LOF mutations on electrogenesis and also to study channel trafficking and pharmacology. Mis et al (2019) recently studied iPSC-Noc from a pair of IEM patients carrying the same Na V 1.7 mutation, with one patient manifesting severe pain and the other manifesting pain resilience. iPSC-Noc cells from both subjects were hyperexcitable.…”

An iPSC Model Reveals Mechanisms of Interindividual Differences in Pain

“…They performed a comparative study on three members of a family affected by IEM: a mother, a father, and a son. The mother and the son both harbor a Na v 1.7 mutation (Na v 1.7-S241T) and experience IEM symptoms, but the pain profile of the son is considerably more severe (Geha et al, 2016;McDonnell et al, 2016;Mis et al, 2019). The father lacks the mutation and is unaffected by IEM.…”