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

Area of Science:

• Neuroscience
• Genetics
• Pain Research

Background:

• Individual differences in pain perception are significant but poorly understood.
• Inherited erythromelalgia (IEM) provides a genetic model for studying chronic pain variability.
• A specific Na_V1.7 mutation causes IEM, leading to hyperexcitable dorsal root ganglion (DRG) neurons.

Purpose of the Study:

• To investigate interindividual differences in pain sensitivity using a family with IEM.
• To model pain sensitivity in vitro using induced pluripotent stem cell (iPSC)-derived sensory neurons.
• To identify genetic variants modulating pain signaling and contributing to pain variability.

Main Methods:

• Generation of subject-specific induced pluripotent stem cells (iPSCs) from family members.
• Differentiation of iPSCs into sensory neurons for in vitro modeling.
• Whole exome sequencing (WES) and dynamic clamp electrophysiology to identify and test gene variants.

Main Results:

• Subject-specific iPSC-derived sensory neurons replicated differential pain sensitivity observed in vivo.
• Peripheral sensory neuron mechanisms were found to contribute to interindividual pain differences.
• A specific variant in the KCNQ gene was identified as modulating neuronal excitability in this family.

Conclusions:

• Subject-specific iPSCs are a viable tool for modeling interindividual pain differences.
• Peripheral mechanisms and specific gene variants significantly influence pain perception.
• The combined approach of iPSCs, WES, and dynamic clamp can pinpoint pain-modulating genetic factors.