Abstract：
BACKGROUND: Xeroderma pigmentosum (XP) is characterized by photosensitivity that causes pigmentary disorder and predisposition to skin cancers on sunlight-exposed areas due to DNA repair deficiency. Patients with XP group A (XP-A) develop freckle-like pigmented maculae and depigmented maculae within a year unless strict sun-protection is enforced. Although it is crucial to study pigment cells (melanocytes: MCs) as disease target cells, establishing MCs in primary cultures is challenging.
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.
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.
摘要：
背景：着色性干皮病（XP）的特征是光敏性，由于DNA修复缺陷，在暴露于阳光的区域引起色素紊乱和皮肤癌倾向。XP组A（XP-A）的患者在一年内出现雀斑样色素性黄斑和色素沉着黄斑，除非实施严格的防晒措施。尽管研究色素细胞（黑色素细胞：MCs）作为疾病靶细胞至关重要，在原代文化中建立MC是具有挑战性的。
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。
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。
