OBJECTIVE: Elucidation of the disease pathogenesis by comparison between MCs differentiated from XP-A induced pluripotent stem cells (iPSCs) and healthy control iPSCs on the response to UV irradiation.
METHODS: iPSCs were established from a XP-A fibroblasts and differentiated into MCs. Differences in gene expression profiles between XP-A-iPSC-derived melanocytes (XP-A-iMCs) and Healthy control iPSC-derived MCs (HC-iMCs) were analyzed 4 and 12 h after irradiation with 30 or 150 J/m2 of UV-B using microarray analysis.
RESULTS: XP-A-iMCs expressed SOX10, MITF, and TYR, and showed melanin synthesis. Further, XP-A-iMCs showed reduced DNA repair ability. Gene expression profile between XP-A-iMCs and HC-iMCs revealed that, numerous gene probes that were specifically upregulated or downregulated in XP-A-iMCs after 150-J/m2 of UV-B irradiation did not return to basal levels. Of note that apoptotic pathways were highly upregulated at 150 J/m2 UV exposure in XP-A-iMCs, and cytokine-related pathways were upregulated even at 30 J/m2 UV exposure.
CONCLUSIONS: We revealed for the first time that cytokine-related pathways were upregulated even at low-dose UV exposure in XP-A-iMCs. Disease-specific iPSCs are useful to elucidate the disease pathogenesis and develop treatment strategies of XP.
目的:通过比较XP-A诱导多能干细胞(iPSCs)分化的MC和健康对照iPSCs对紫外线照射的反应,阐明疾病的发病机理。
方法:从XP-A成纤维细胞中建立iPSC并分化成MC。在用30或150J/m2的UV-B照射后4和12小时,使用微阵列分析分析XP-A-iPSC衍生的黑素细胞(XP-A-iMCs)和健康对照iPSC衍生的MC(HC-iMCs)之间的基因表达谱差异。
结果:XP-A-iMC表示SOX10,MITF,还有TYR,并显示黑色素合成。Further,XP-A-iMC显示降低的DNA修复能力。XP-A-iMCs和HC-iMCs之间的基因表达谱显示,在150-J/m2的UV-B照射后,在XP-A-iMC中特异性上调或下调的许多基因探针没有恢复到基础水平。值得注意的是,在XP-A-iMC中,凋亡途径在150J/m2紫外线照射下高度上调,甚至在30J/m2UV暴露时,细胞因子相关途径也上调。
结论:我们首次揭示了即使在低剂量紫外线照射下,XP-A-iMC中细胞因子相关途径也上调。疾病特异性iPSCs可用于阐明疾病的发病机制和开发XP的治疗策略。