Division of Dermatology, Department of Internal Related, Graduate School of Medicine, Kobe University, Kobe, Japan.
Division of Stem Cell Medicine, Graduate School of Medicine, Kobe University, Kobe, Japan; Division of Advanced Medical Science, Graduate School of Science, Technology and Innovation, Kobe University, Kobe, Japan; Center for Human Resource development for Regenerative Medicine, Kobe University Hospital, Kobe, Japan.
J Dermatol Sci. 2024 Sep;115(3):111-120. doi: 10.1016/j.jdermsci.2024.06.004. Epub 2024 Jun 22.
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/m 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/m of UV-B irradiation did not return to basal levels. Of note that apoptotic pathways were highly upregulated at 150 J/m UV exposure in XP-A-iMCs, and cytokine-related pathways were upregulated even at 30 J/m 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.
着色性干皮病（XP）的特征是对 DNA 修复缺陷导致的阳光照射部位的色素紊乱和皮肤癌易感性。XP-A 组患者在未严格防晒的情况下，一年内会发展出雀斑样色素斑和色素减退斑。虽然研究疾病靶细胞——色素细胞（黑素细胞：MC）至关重要，但建立原代培养的 MC 具有挑战性。
通过比较 XP-A 诱导多能干细胞（iPSC）分化的 MC 和健康对照 iPSC 对 UV 照射的反应，阐明疾病发病机制。
从 XP-A 成纤维细胞中建立 iPSC，并分化为 MC。用微阵列分析，在 30 或 150 J/m2 的 UV-B 照射后 4 和 12 小时，分析 XP-A-iPSC 衍生的黑素细胞（XP-A-iMC）和健康对照 iPSC 衍生的 MC（HC-iMC）之间的基因表达谱差异。
XP-A-iMC 表达 SOX10、MITF 和 TYR，并表现出黑色素合成。此外，XP-A-iMC 显示出降低的 DNA 修复能力。XP-A-iMC 和 HC-iMC 之间的基因表达谱显示，在 150-J/m2 的 UV-B 照射后，许多在 XP-A-iMC 中特异性上调或下调的基因探针并未恢复到基础水平。值得注意的是，在 XP-A-iMC 中，150 J/m2 的 UV 照射下，凋亡途径高度上调，即使在 30 J/m2 的 UV 照射下，细胞因子相关途径也上调。
我们首次揭示，即使在低剂量 UV 照射下，细胞因子相关途径在 XP-A-iMC 中也上调。疾病特异性 iPSC 可用于阐明疾病发病机制并开发 XP 的治疗策略。
