Preclinical research using different rodent model systems has largely contributed to the scientific progress in the pain field, however, it suffers from interspecies differences, limited access to human models, and ethical concerns. Human induced pluripotent stem cells (iPSCs) offer major advantages over animal models, i.e., they retain the genome of the donor (patient), and thus allow donor-specific and cell-type specific research. Consequently, human iPSC-derived nociceptors (iDNs) offer intriguingly new possibilities for patient-specific, animal-free research. In the present study, we characterized iDNs based on the expression of well described nociceptive markers and ion channels, and we conducted a side-by-side comparison of iDNs with mouse sensory neurons. Specifically, immunofluorescence (IF) analyses with selected markers including early somatosensory transcription factors (BRN3A/ISL1/RUNX1), the low-affinity nerve growth factor receptor (p75), hyperpolarization-activated cyclic nucleotide-gated channels (HCN), as well as high voltage-gated calcium channels (VGCC) of the Ca_V2 type, calcium permeable TRPV1 channels, and ionotropic GABA_A receptors, were used to address the characteristics of the iDN phenotype. We further combined IF analyses with microfluorimetric Ca²⁺ measurements to address the functionality of these ion channels in iDNs. Thus, we provide a detailed morphological and functional characterization of iDNs, thereby, underpinning their enormous potential as an animal-free alternative for human specific research in the pain field for unveiling pathophysiological mechanisms and for unbiased, disease-specific personalized drug development.

中文翻译：

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选定的离子受体和电压门控离子通道：人类诱导的多能干细胞（iPSC）衍生伤害感受器的更多功能能力。

使用不同啮齿动物模型系统的临床前研究在很大程度上促进了疼痛领域的科学进步，但是，它存在种间差异，使用人类模型的机会有限以及道德方面的问题。与动物模型相比，人类诱导的多能干细胞（iPSC）具有主要优势，即它们保留了供体（患者）的基因组，因此可以进行特定于供体和细胞类型的研究。因此，人类iPSC衍生的伤害感受器（iDN）为特定于患者的无动物研究提供了新的可能性。在本研究中，我们基于描述良好的伤害性标志物和离子通道的表达来表征iDN，并进行了iDN与小鼠感觉神经元的并排比较。特别，_V 2型，钙可渗透的TRPV1通道和离子型GABA _A受体用于解决iDN表型的特征。我们进一步将IF分析与微荧光Ca ²⁺测量相结合，以解决iDN中这些离子通道的功能。因此，我们提供了iDN的详细形态和功能表征，从而支持了它们作为无痛动物替代品的巨大潜力，可用于疼痛领域中的人类特定研究，以揭示病理生理机制和无偏见，针对疾病的个性化药物开发。