TY - JOUR
T1 - Congenital pituitary hypoplasia model demonstrates hypothalamic OTX2 regulation of pituitary progenitor cells
AU - Matsumoto, Ryusaku
AU - Suga, Hidetaka
AU - Aoi, Takashi
AU - Bando, Hironori
AU - Fukuoka, Hidenori
AU - Iguchi, Genzo
AU - Narumi, Satoshi
AU - Hasegawa, Tomonobu
AU - Muguruma, Keiko
AU - Ogawa, Wataru
AU - Takahashi, Yutaka
N1 - Funding Information:
We are grateful to Y. Oiso at Nagoya University and T. Yamamoto at Kyoto University for their support, N. Matsumoto at Yokohama City University for exome sequencing analysis, and the members of the Takahashi, Suga, and Aoi laboratories for valuable discussions. This work was supported by grants from the Japan Agency for Medical Research and Development (AMED; The Acceleration Program for Intractable Disease Research Utilizing Disease-specific iPS Cells: JP 18bm0804012h0002), grants-in-aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology (17K19684 and 16H05332 to YT and 18K16232 to RM), grants from the Uehara Memorial Foundation and the Naito Foundation, and the Program for Intractable Disease Research Utilizing Disease-specific iPS Cells of the Japan Science and Technology Agency/AMED (16bm0609002h0105 to KM).
Publisher Copyright:
© 2020, American Society for Clinical Investigation.
PY - 2020/2/3
Y1 - 2020/2/3
N2 - 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 3D 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.
AB - 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 3D 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.
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U2 - 10.1172/JCI127378
DO - 10.1172/JCI127378
M3 - Article
C2 - 31845906
AN - SCOPUS:85078868392
SN - 0021-9738
VL - 130
SP - 641
EP - 654
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 2
ER -