Development of a functional thyroid model based on an organoid culture system

Yoshiyuki Saito; Nobuyuki Onishi; Hiroshi Takami; Ryo Seishima; Hiroyoshi Inoue; Yuki Hirata; Kaori Kameyama; Kenji Tsuchihashi; Eiji Sugihara; Shinya Uchino; Koichi Ito; Hirofumi Kawakubo; Hiroya Takeuchi; Yuko Kitagawa; Hideyuki Saya; Osamu Nagano

doi:10.1016/j.bbrc.2018.02.154

Development of a functional thyroid model based on an organoid culture system

Biochem Biophys Res Commun. 2018 Mar 4;497(2):783-789. doi: 10.1016/j.bbrc.2018.02.154. Epub 2018 Feb 19.

Authors

Affiliations

¹ Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan; Department of Surgery, School of Medicine, Keio University, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan.
² Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan.
³ Department of Surgery, Ito Hospital, 4-3-6 Jingumae, Shibuya-ku, Tokyo 150-8308, Japan.
⁴ Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan; Department of Surgery, School of Medicine, Keio University, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan; A*STAR Institute of Medical Biology, 8A Biomedical Grove, #06-06 Immunos 138648, Singapore.
⁵ Department of Chemistry, School of Medicine, Keio University, 4-1-1 Hiyoshi, Kohoku-ku, Kanagawa 223-8521, Japan.
⁶ Department of Pathology, School of Medicine, Keio University, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan.
⁷ Surgical Department, Noguchi Thyroid Clinic and Hospital Foundation, 7-52 Aoyama-cho, Beppu, Oita 874-0902, Japan.
⁸ Department of Surgery, School of Medicine, Keio University, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan.
⁹ Department of Surgery, School of Medicine, Keio University, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan; Department of Surgery, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka 431-3192, Japan.
¹⁰ Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan. Electronic address: osmna@sb3.so-net.ne.jp.

PMID: 29470983
DOI: 10.1016/j.bbrc.2018.02.154

Abstract

The low turnover rate of thyroid follicular cells and the lack of a long-term thyroid cell culture system have hampered studies of thyroid carcinogenesis. We have now established a thyroid organoid culture system that supports thyroid cell proliferation in vitro. The established mouse thyroid organoids performed thyroid functions including thyroglobulin synthesis, iodide uptake, and the production and release of thyroid hormone. Furthermore, transplantation of the organoids into recipient mice resulted in the formation of normal thyroid-like tissue capable of iodide uptake and thyroglobulin production in vivo. Finally, forced expression of oncogenic NRAS (NRAS^Q61R) in thyroid organoids established from p53 knockout mice and transplantation of the manipulated organoids into mouse recipients generated a model of poorly differentiated thyroid cancer. Our findings suggest that this newly developed thyroid organoid culture system is a potential research tool for the study of thyroid physiology and pathology including thyroid cancer.

Keywords: NRAS; Organoid; Thyroid; Thyroid cancer model; p53.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Female
GTP Phosphohydrolases / genetics
Gene Expression Regulation, Neoplastic
Humans
Membrane Proteins / genetics
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Knockout
Mice, SCID
Mice, Transgenic
Organ Culture Techniques / methods*
Organoids / cytology*
Organoids / pathology
Organoids / physiology
Point Mutation
Thyroid Gland / cytology*
Thyroid Gland / pathology
Thyroid Gland / physiology
Thyroid Neoplasms / genetics
Thyroid Neoplasms / pathology
Tumor Suppressor Protein p53 / genetics

Substances

Membrane Proteins
Tumor Suppressor Protein p53
GTP Phosphohydrolases
NRAS protein, human