Pattern of Functional TTX-Resistant Sodium Channels Reveals a Developmental Stage of Human iPSC- and ESC-Derived Nociceptors

Stem Cell Reports
Esther EberhardtAngelika Lampert

Abstract

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.

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Citations

Feb 6, 2017·Molecular Therapy : the Journal of the American Society of Gene Therapy·Steven HavlicekLawrence W Stanton
Jul 25, 2017·BioResearch Open Access·Takaharu NegoroAkifumi Matsuyama
Jan 24, 2019·Physiological Reviews·David L BennettSulayman D Dib-Hajj
Sep 7, 2018·Frontiers in Molecular Neuroscience·Marília Z P GuimarãesStevens K Rehen
Sep 26, 2019·Frontiers in Neuroscience·Jianying HuangSulayman D Dib-Hajj
Jun 30, 2019·Disease Models & Mechanisms·Lucie ValekIrmgard Tegeder
Dec 23, 2020·Tissue Engineering. Part C, Methods·Stacey C SchutteSteve Davidson
Dec 29, 2020·Frontiers in Cellular Neuroscience·Amy J HulmeMirella Dottori
Jun 16, 2021·Brain : a Journal of Neurology·Steven J MiddletonDavid L Bennett
Jun 22, 2021·Annual Review of Biochemistry·Marcin SzczotAlexander T Chesler
Nov 11, 2021·Science Translational Medicine·Selwyn JayakarClifford J Woolf

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Methods Mentioned

BETA
biopsies
Transfection
PCRs

Software Mentioned

HEKA
PatchMaster
GraphPad Prism
pClamp
Origin

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