色素性干皮病 (XP) 的特点是光敏性，会导致色素紊乱，并且由于 DNA 修复缺陷而导致暴露在阳光下的区域容易患皮肤癌。 XP A 组 (XP-A) 患者如果不严格防晒，一年内会出现雀斑样色素斑和色素脱失斑。尽管研究色素细胞（黑素细胞：MC）作为疾病靶细胞至关重要，但在原代培养物中建立 MC 具有挑战性。通过比较 XP-A 诱导多能干细胞 (iPSC) 分化的 MC 与健康对照，阐明疾病发病机制iPSC 对紫外线照射的反应。iPSC 由 XP-A 成纤维细胞建立并分化为 MC。在 30 或 150J/m2 紫外线照射后 4 小时和 12 小时，分析 XP-A-iPSC 衍生黑素细胞 (XP-A-iMC) 和健康对照 iPSC 衍生 MC (HC-iMC) 之间基因表达谱的差异-B 使用微阵列分析。XP-A-iMC 表达 SOX10、MITF 和 TYR，并显示黑色素合成。此外，XP-A-iMCs 显示 DNA 修复能力降低。 XP-A-iMC 和 HC-iMC 之间的基因表达谱显示，在 150 J/m2 UV-B 照射后，XP-A-iMC 中特异性上调或下调的许多基因探针并未恢复到基础水平。值得注意的是，XP-A-iMCs 中的细胞凋亡途径在 150J/m2 紫外线照射下高度上调，细胞因子相关途径甚至在 30J/m2 紫外线照射下也上调。我们首次揭示了细胞因子相关途径在即使在 XP-A-iMC 中低剂量紫外线照射下，其表达也会上调。疾病特异性 iPSC 可用于阐明疾病发病机制并制定 XP 治疗策略。版权所有 © 2024 日本皮肤病研究学会。由 Elsevier B.V. 出版。保留所有权利。

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.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.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.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.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.Copyright © 2024 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.