Congenital pituitary hypoplasia model demonstrates hypothalamic OTX2 regulation of pituitary progenitor cells
Congenital pituitary hypoplasia model demonstrates hypothalamic OTX2 regulation of pituitary progenitor cells
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DOI：
10.1172/jci127378
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发表时间：
2020-02-03
影响因子：
15.9
通讯作者：
Takahashi, Yutaka
中科院分区：
文献类型：
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作者：
Matsumoto, Ryusaku;Suga, Hidetaka;Takahashi, Yutaka
下丘脑腹侧部与下丘脑腹侧部相连，由口部外胚层发育而成。这一过程的损害导致先天性垂体发育不全（CPH）;然而，迄今为止还没有CPH的人类疾病模型，无法阐明潜在的机制。在这项研究中，我们建立了一个疾病模型的CPH使用患者来源的诱导多能干细胞（iPSCs）和30类器官技术，其中口腔外胚层和下丘脑同时发育。有趣的是，在正齿同源异型框2（OTX 2）基因中具有杂合突变的患者iPSC显示垂体祖细胞中的凋亡增加，并且分化成垂体前叶产生细胞严重受损。作为一种潜在的机制，下丘脑中的OTX 2而不是口腔外胚层中的OTX 2通过下丘脑中的FGF 10表达调节口腔外胚层中的LHX 3表达而对祖细胞维持是必需的。令人信服的是，表型通过突变的校正而逆转，并且对照iPSC中的OTX 2的单倍不足揭示了类似的表型，表明该突变是负责的。因此，我们建立了基于iPSC的先天性垂体疾病模型，其再现了下丘脑和口腔外胚层之间的相互作用，并证明了下丘脑OTX 2的重要作用。
Pituitary develops from oral ectoderm in contact with adjacent ventral hypothalamus. Impairment in this process results in congenital pituitary hypoplasia (CPH); however, there have been no human disease models for CPH thus far, prohibiting the elucidation of the underlying mechanisms. In this study, we established a disease model of CPH using patient-derived induced pluripotent stem cells (iPSCs) and 30 organoid technique, in which oral ectoderm and hypothalamus develop simultaneously. Interestingly, patient iPSCs with a heterozygous mutation in the orthodenticle homeobox 2 (OTX2) gene showed increased apoptosis in the pituitary progenitor cells, and the differentiation into pituitary hormone-producing cells was severely impaired. As an underlying mechanism, OTX2 in hypothalamus, not in oral ectoderm, was essential for progenitor cell maintenance by regulating LHX3 expression in oral ectoderm via FGF10 expression in the hypothalamus. Convincingly, the phenotype was reversed by the correction of the mutation, and the haploinsufficiency of OTX2 in control iPSCs revealed a similar phenotype, demonstrating that this mutation was responsible. Thus, we established an iPSC-based congenital pituitary disease model, which recapitulated interaction between hypothalamus and oral ectoderm and demonstrated the essential role of hypothalamic OTX2.