Institute of Physiology and Pathophysiology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Universitätsstraße 17, 91054 Erlangen, Germany; Department of Anesthesiology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Krankenhausstrasse 12, 91054 Erlangen, Germany.
IZKF Junior Research Group and BMBF Research Group Neuroscience, IZKF, Friedrich-Alexander-Universität Erlangen-Nürnberg, Glückstrasse 6, 91054 Erlangen, Germany.
Stem Cell Reports. 2015 Sep 8;5(3):305-13. doi: 10.1016/j.stemcr.2015.07.010. Epub 2015 Aug 28.
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.
人类多能干细胞 (hPSCs) 提供了生成神经元细胞的机会,包括伤害感受器。我们使用基于化学的方法,从 HUES6 胚胎干细胞和逆转录病毒重编程的源自成纤维细胞的诱导 hPSCs 中生成伤害感受感觉神经元。伤害感受器神经元表达各自的标记物,并在膜片钳实验中显示河豚毒素敏感 (TTXs) 和 -抗性 (TTXr) 电压门控钠电流。与来自啮齿动物背根神经节的对应物相比,hPSC 衍生的伤害感受器的 TTXr 电流出人意料地表现出明显更超极化的激活和快速失活的电压依赖性。这种明显的差异很可能是由于发育重要的钠通道 NAV1.5 的大量表达。鉴于在动物模型中重现神经性疼痛的障碍,我们的数据推进了 hPSC 衍生的伤害感受器作为研究人类伤害感受器神经元发育和发病机制过程以及开发更具特异性的小分子来减轻疼痛的更好模型。