TY - JOUR
T1 - Pattern of Functional TTX-Resistant Sodium Channels Reveals a Developmental Stage of Human iPSC- and ESC-Derived Nociceptors
AU - Eberhardt, Esther
AU - Havlicek, Steven
AU - Schmidt, Diana
AU - Link, Andrea S.
AU - Neacsu, Cristian
AU - Kohl, Zacharias
AU - Hampl, Martin
AU - Kist, Andreas M.
AU - Klinger, Alexandra
AU - Nau, Carla
AU - Schüttler, Jürgen
AU - Alzheimer, Christian
AU - Winkler, Jürgen
AU - Namer, Barbara
AU - Winner, Beate
AU - Lampert, Angelika
N1 - Funding Information:
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.
Publisher Copyright:
© 2015 The Authors.
Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.
PY - 2015/9/8
Y1 - 2015/9/8
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84941174537&partnerID=8YFLogxK
U2 - 10.1016/j.stemcr.2015.07.010
DO - 10.1016/j.stemcr.2015.07.010
M3 - Journal articles
C2 - 26321143
AN - SCOPUS:84941174537
SN - 2213-6711
VL - 5
SP - 305
EP - 313
JO - Stem Cell Reports
JF - Stem Cell Reports
IS - 3
ER -
