Functional Lactotrophs in Induced Adenohypophysis Differentiated From Human iPS Cells.

Prolactin (PRL), a hormone involved in lactation, is mainly produced and secreted by the lactotrophs of the anterior pituitary (AP) gland. We previously reported a method to generate functional adrenocorticotropic hormone-producing cells by differentiating the AP and hypothalamus simultaneously from human induced pluripotent stem cells (iPSCs). However, PRL-producing cells in the induced AP have not been investigated. Here, we confirmed the presence of PRL-producing cells and evaluated their endocrine functions. We differentiated pituitary cells from human iPSCs using serum-free floating culture of embryoid-like aggregates with quick reaggregation (SFEB-q) method and evaluated the appearance and function of PRL-producing cells. Secretion of PRL from the differentiated aggregates was confirmed, which increased with further culture. Fluorescence immunostaining and immunoelectron microscopy revealed PRL-producing cells and PRL-positive secretory granules, respectively. PRL secretion was promoted by various prolactin secretagogues such as thyrotropin-releasing hormone, vasoactive intestinal peptide, and prolactin-releasing peptide, and inhibited by bromocriptine. Moreover, the presence of tyrosine hydroxylase-positive dopaminergic nerves in the hypothalamic tissue area around the center of the aggregates connecting to PRL-producing cells indicated the possibility of recapitulating PRL regulatory mechanisms through the hypothalamus. In conclusion, we generated pituitary lactotrophs from human iPSCs; these displayed similar secretory responsiveness as human pituitary cells in vivo. In the future, this is expected to be used as a model of human PRL-producing cells for various studies, such as drug discovery, prediction of side effects, and elucidation of tumorigenic mechanisms using disease-specific iPSCs. Furthermore, it may help to develop regenerative medicine for the pituitary gland. © The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Citation

Natsuki Miyake, Takashi Nagai, Hidetaka Suga, Satoko Osuka, Takatoshi Kasai, Mayu Sakakibara, Mika Soen, Hajime Ozaki, Tsutomu Miwata, Tomoyoshi Asano, Mayuko Kano, Ayako Muraoka, Natsuki Nakanishi, Tomoko Nakamura, Maki Goto, Yoshinori Yasuda, Yohei Kawaguchi, Takashi Miyata, Tomoko Kobayashi, Mariko Sugiyama, Takeshi Onoue, Daisuke Hagiwara, Shintaro Iwama, Akira Iwase, Naoko Inoshita, Hiroshi Arima, Hiroaki Kajiyama. Functional Lactotrophs in Induced Adenohypophysis Differentiated From Human iPS Cells. Endocrinology. 2022 Mar 01;163(3)

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PMID: 35085394

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