Modelling neuropathic pain in vitro: a multimodal approach using induced-pluripotent stem cell-derived sensory neurons and mechanically compressed keratinocytes
Abstract
Neuropathic pain is a chronic pain disorder arising from a dysfunction of the somatosensory nervous system, often resulting in altered activity of voltage-gated sodium channels (Nav). However, the molecular mechanism is complex and not fully understood. Therefore, this thesis investigated the development of advanced in vitro models for neuropathic pain, with a focus on sensory neurons and the keratinocytes surrounding them in the skin. Human induced pluripotent stem cells (iPSCs) reprogrammed from somatic cells of healthy individuals and neuropathic pain patients offer a unique opportunity to obtain human sensory neurons harboring the donor’s genotype. IPSC-derived sensory neurons have been successfully used to model phenotypes of small fiber neuropathy (SFN) patients with mutations in Nav1.7. The tetrodotoxin-resistant (TTXr) channels Nav1.8 and Nav1.9 critically modulate nociceptor excitability, and variants have been linked to neuropathic pain. However, the functional presence of Nav1.8 and Nav1.9 in iPSC-derived sensory neurons is unclear. Here, iPSCs from two SFN patients with a putative pathogenic Nav1.9-Y66S variant were employed to evaluate iPSC-sensory neurons as neuropathic pain models, focusing on TTX-resistant currents, neuronal excitability, and action potential characteristics, as well as modelling of the Nav1.9-Y66S phenotype. The three iPSC-sensory neuron differentiation protocols employed – small-molecule- or transcription factor overexpression-driven –…
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