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.
Silk fibroin (SF) is a biocompatible and slowly biodegradable material with excellent mechanical properties and huge potential for use as biofunctional interface in electronic devices that aim to stimulate and control neural network activity and peripheral nerve repair. It is shown that SF films act as material interfaces that support the adherence and neurite outgrowth of dorsal root ganglion (DRG) neurons and preserve neuronal functions. Silk films preserve the capability of neuronal cells to fire and DRG neurons on silk films retain the intracellular free Ca2+ concentration ([Ca2+]i) response to capsaicin, a typical noxious stimulus for this neuronal culture model. It is also demonstrated that nerve growth factor (NGF)‐functionalized silk films promote neurite outgrowth and modulate functional properties of DRG neurons. The results show that silk preserves DRG neuronal physiology and is a promising biomaterial platform for the future development of devices with goals including functional recovery of injured neurons, neurite functional outgrowth in vitro, or functional electrostimulation in vivo.
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