Abstract
Summary Human pluripotent stem cells (hPSCs) offer the opportunity to generate neuronal cells, including nociceptors. Using a chemical-based approach, we generated nociceptive sensory neurons from HUES6 embryonic stem cells and retrovirally reprogrammed induced hPSCs derived from fibroblasts. The nociceptive neurons expressed respective markers and showed tetrodotoxin-sensitive (TTXs) and -resistant (TTXr) voltage-gated sodium currents in patch-clamp experiments. In contrast to their counterparts from rodent dorsal root ganglia, TTXr currents of hPSC-derived nociceptors unexpectedly displayed a significantly more hyperpolarized voltage dependence of activation and fast inactivation. This apparent discrepancy is most likely due to a substantial expression of the developmentally important sodium channel NAV1.5. In view of the obstacles to recapitulate neuropathic pain in animal models, our data advance hPSC-derived nociceptors as a better model to study developmental and pathogenetic processes in human nociceptive neurons and to develop more specific small molecules to attenuate pain. This study investigates detailed electrophysiological characteristics of hPSC-derived peripheral nociceptive neurons with focus on voltage-gated sodium channels. Besides the pain-relevant subtypes NAV1.8 and NAV1.9, Lampert, Winner, and colleagues find that significant amounts of the developmentally important NAV1.5 are expressed and functionally active. Thus, human hPSC-derived nociceptors offer a suitable model of developing sensory neurons.
| Original language | English |
|---|---|
| Journal | Stem Cell Reports |
| Volume | 5 |
| Issue number | 3 |
| Pages (from-to) | 305-313 |
| Number of pages | 9 |
| ISSN | 2213-6711 |
| DOIs | |
| Publication status | Published - 08.09.2015 |
Funding
This work was supported by the Johannes and Frieda Marohn-Foundation (Win/2012). Additional funding came from the German Federal Ministry of Education and Research (BMBF, 01GQ113 to B.W.), the Bavarian Ministry of Sciences, Research and the Arts in the framework of the Bavarian Molecular Biosystems Reseach Network (to B.W.) and the ForIPS network (to B.W., Z.K., J.W.), the Interdisciplinary Center for Clinical Research (University Hospital Erlangen to B.W.), the Bavarian Research Foundation (PIZ-180-10), the German-Israeli-Foundation (GIF, 1091-27.1/2010 to A.L.), and the German Research Association (DFG LA2740/2-1 to A.L., NA 970 1/1 to B.N., INST 90/675-1 FUGG to C.A.) and the Jürgen Manchot Stiftung (PhD fellowship to A.S.L.). The present work was performed in fulfillment of the requirements for obtaining the degree “Dr. med.” (E.E.). We thank Holger Wend, Sonja Plötz, Iwona Izydorczyk, and Michaela Hellwig for excellent technical support.
