Schoepf Clemens L, Zeidler Maximilian, Spiecker Lisa, Kern Georg, Lechner Judith, Kummer Kai K, Kress Michaela
Institute of Physiology, Medical University of Innsbruck, 6020 Innsbruck, Austria.
Brain Sci. 2020 Jun 3;10(6):344. doi: 10.3390/brainsci10060344.
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 Ca2 type, calcium permeable TRPV1 channels, and ionotropic GABA receptors, were used to address the characteristics of the iDN phenotype. We further combined IF analyses with microfluorimetric Ca 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.
使用不同啮齿动物模型系统的临床前研究在很大程度上推动了疼痛领域的科学进展,然而,它存在种间差异、难以获得人类模型以及伦理问题。人类诱导多能干细胞(iPSC)相对于动物模型具有主要优势,即它们保留了供体(患者)的基因组,因此允许进行供体特异性和细胞类型特异性研究。因此,人类iPSC衍生的伤害感受器(iDN)为患者特异性、无动物研究提供了极具吸引力的新可能性。在本研究中,我们根据已充分描述的伤害感受标记物和离子通道的表达对iDN进行了表征,并将iDN与小鼠感觉神经元进行了并列比较。具体而言,使用针对包括早期躯体感觉转录因子(BRN3A/ISL1/RUNX1)、低亲和力神经生长因子受体(p75)、超极化激活环核苷酸门控通道(HCN)以及Ca2型高电压门控钙通道(VGCC)、钙通透性TRPV1通道和离子型GABA受体等选定标记物的免疫荧光(IF)分析来研究iDN表型的特征。我们进一步将IF分析与微量荧光钙测量相结合,以研究这些离子通道在iDN中的功能。因此,我们提供了iDN详细的形态学和功能表征,从而支持了它们作为无动物替代物在疼痛领域进行人类特异性研究的巨大潜力,以揭示病理生理机制并进行无偏见的、疾病特异性的个性化药物开发。