Identification of adreno-gonadal primordium from human iPSC and elucidation of its differentiation pathway

• Project/Area Number: 17K09880
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Endocrinology
• Research Institution: Kyoto University
• Principal Investigator: Sone Masakatsu 京都大学, 医学研究科, 特定准教授 (40437207)
• Co-Investigator(Kenkyū-buntansha): 田浦 大輔 京都大学, 医学研究科, 特定助教 (10558612)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: adrenal / gonad / iPS / ステロイドホルモン / 副腎皮質 / 性腺 / ヒトiPS細胞 / adrenal cortex / steroid hormone / iPS cell / adrenal cortex, / gonad, / 再生医学 / 細胞・組織 / 内分泌学 / 副腎

Outline of Final Research Achievements

We tried to elucidate the steroidogenic differentiation processes using hiPSC-derived intermediate mesoderm (IM) that is known to be the origin of the human adrenal cortex and gonads. IM cells expressing Odd-skipped related 1 (OSR1), an early IM marker, were sorted and transfected with steroidogenic factor-1 (SF-1) /adrenal 4 binding protein. Analysis of OSR1+ cells transfected with SF-1 revealed that dopamine D1 receptor agonist upregulated expression of various steroidogenic enzymes and increased secretion of steroid hormones synergistically with adrenocorticotropic hormone. These OSR1+ cells transfected with SF-1 secreted both gonadal and adrenal steroid hormones. 3-dimensional culture of these cells upregulated the expression of various steroidogenic enzymes. We are now trying to elucidate the mechanism of organ-specific differentiation into gonadal cells and adrenocortical cells.

Academic Significance and Societal Importance of the Research Achievements

我々は、世界で初めてヒトiPS細胞から中間中胚葉を経て副腎皮質ステロイド産生細胞を誘導することに成功しており、本研究はその手法のさらなる発展とin vitroでの発生研究への応用を目指したものである。ヒトiPS細胞を利用することによりヒトの発生・分化メカニズムをin vitroで解明することを目指したもので学術的意義は高く、また将来の副腎・性腺の再生療法への応用も考えられるため社会的意義も高い。

Research Products

• [Journal Article] Human iPS cell-derived mural cells as an in vitro model of hereditary cerebral small vessel disease (2020)
  • Author(s): Yamamoto Yumi、Kojima Katsutoshi、Taura Daisuke、Sone Masakatsu、Washida Kazuo、Egawa Naohiro、Kondo Takayuki、Minakawa Eiko N.、Tsukita Kayoko、Enami Takako、Tomimoto Hidekazu、Mizuno Toshiki、Kalaria Raj N.、Inagaki Nobuya、Takahashi Ryosuke、Harada-Shiba Mariko、Ihara Masafumi、Inoue Haruhisa
  • Journal Title: Molecular Brain Volume: 13 Issue: 1 Pages: 38-38
  • DOI: 10.1186/s13041-020-00573-w
  • NAID: 120006818682
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Nadir Aldosterone Levels After Confirmatory Tests Are Correlated With Left Ventricular Hypertrophy in Primary Aldosteronism. (2020)
  • Author(s): Ohno Y, Sone M, Inagaki N, Kawashima A, Takeda Y, Yoneda T, Kurihara I, Itoh H, Tsuiki M, Ichijo T, Katabami T, Wada N, Sakamoto R, Ogawa Y, Yoshimoto T, Yamada T, Kawashima J, Matsuda Y, Kobayashi H, Kamemura K, Yamamoto K, Otsuki M, Okamura S, Izawa S, Okamoto R, Tamura K, Tanabe A, Naruse M; JPAS/JRAS Study Group*.
  • Journal Title: Hypertension. Volume: - Issue: 6 Pages: 1475-1482
  • DOI: 10.1161/hypertensionaha.119.14601
  • Peer Reviewed
• [Journal Article] A Modular Differentiation System Maps Multiple Human Kidney Lineages from Pluripotent Stem Cells. (2020)
  • Author(s): Tsujimoto H, Kasahara T, Sueta SI, Araoka T, Sakamoto S, Okada C, Mae SI, Nakajima T, Okamoto N, Taura D, Nasu M, Shimizu T, Ryosaka M, Li Z, Sone M, Ikeya M, Watanabe A, Osafune K.
  • Journal Title: Cell Rep. Volume: 31 Issue: 1 Pages: 107476-107476
  • DOI: 10.1016/j.celrep.2020.03.040
  • NAID: 120006823939
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Latent Autonomous Cortisol Secretion From Apparently Nonfunctioning Adrenal Tumor in Nonlateralized Hyperaldosteronism. (2019)
  • Author(s): Ohno Y, Sone M, Inagaki N, Takeda Y, Kurihara I, Tsuiki M, Ichijo T, Wada N, Katabami T, Ogawa Y, Okamura S, Fukuoka T, Kai T, Izawa S, Yoshikawa Y, Hashimoto S, Yamada M, Chiba Y, Naruse M; JPAS/JRAS Study Group.
  • Journal Title: J Clin Endocrinol Metab. Volume: 104 Issue: 10 Pages: 4382-4389
  • DOI: 10.1210/jc.2018-02790
  • Peer Reviewed
• [Journal Article] Renal impairment is closely associated with plasma aldosterone concentration in patients with primary aldosteronism. (2019)
  • Author(s): Kawashima A, Sone M, Inagaki N, Takeda Y, Itoh H, Kurihara I, Umakoshi H, Ichijo T, Katabami T, Wada N, Ogawa Y, Kawashima J, Fujita M, Miyauchi S, Okamura S, Fukuoka T, Yanase T, Izawa S, Yoshikawa Y, Hashimoto S, Yamada M, Kai T, Suzuki T, Naruse M.
  • Journal Title: Eur J Endocrinol. Volume: 181 Issue: 3 Pages: 339-350
  • DOI: 10.1530/eje-19-0047
  • Peer Reviewed
• [Journal Article] Reversal of Cushing Pigmentation by Sunitinib. (2019)
  • Author(s): Iwasaki Y, Sone M, Inagaki N.
  • Journal Title: J Endocr Soc. Volume: 3(4) Issue: 4 Pages: 714-715
  • DOI: 10.1210/js.2018-00415
  • Peer Reviewed / Open Access
• [Journal Article] Prevalence of Cardiovascular Disease and Its Risk Factors in Primary Aldosteronism: A Multicenter Study in Japan. (2018)
  • Author(s): Ohno, Y., Sone, M., Inagaki, N., Yamasaki, T., Ogawa, O., Takeda, Y., Kurihara, I., Itoh, H., Umakoshi, H., Tsuiki, M., et al.
  • Journal Title: Hypertension Volume: 71 Issue: 3 Pages: 530-537
  • DOI: 10.1161/hypertensionaha.117.10263
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Obesity as a Key Factor Underlying Idiopathic Hyperaldosteronism. (2018)
  • Author(s): Ohno Y, Sone M, Inagaki N, Yamasaki T, Ogawa O, Takeda Y, Kurihara I, Umakoshi H, Ichijo T, Katabami T, Wada N, Ogawa Y, Yoshimoto T, Kawashima J, Watanabe M, Matsuda Y, Kobayashi H, Shibata H, Miyauchi S, Kamemura K, Fukuoka T, Yamamoto K, Otsuki M, Suzuki T, Naruse M; JPAS Study Group.
  • Journal Title: J Clin Endocrinol Metab. Volume: 103(12) Issue: 12 Pages: 4456-4464
  • DOI: 10.1210/jc.2018-00866
  • Peer Reviewed
• [Journal Article] Evaluation of quantitative parameters for distinguishing pheochromocytoma from other adrenal tumors. (2018)
  • Author(s): Ohno Y, Sone M, Taura D, Yamasaki T, Kojima K, Honda-Kohmo K, Fukuda Y, Matsuo K, Fujii T, Yasoda A, Ogawa O, Inagaki N.
  • Journal Title: Hypertension Research Volume: 41 Issue: 3 Pages: 165-175
  • DOI: 10.1038/s41440-017-0002-4
  • Peer Reviewed
• [Journal Article] Significance of dopamine D1 receptor signalling for steroidogenic differentiation of human induced pluripotent stem cells. (2017)
  • Author(s): Matsuo K, Sone M, Honda-Kohmo K, Toyohara T, Sonoyama T, Taura D, Kojima K, Fukuda Y, Ohno Y, Inoue M, Ohta A, Osafune K, Nakao K, Inagaki N.
  • Journal Title: Sci Rep. Volume: Nov 9;7(1) Issue: 1 Pages: 15120-15120
  • DOI: 10.1038/s41598-017-15485-4
  • Peer Reviewed / Open Access
• [Presentation] Significance Of Dopamine D1 Receptor Signaling For Steroidogenic Differentiation Of Human Induced Pluripotent Stem Cells (2017)
  • Author(s): Koji Matsuo, Masakatsu Sone, Kyoko Honda-Kohmo, Takafumi Toyohara, Takuhiro Sonoyama, Daisuke Taura, Katsutoshi Kojima, Yorihide Fukuda, Youichi Ohno, Mayumi Inoue, Akira Ohta, Kenji Osafune, Kazuwa Nakao, Nobuya Inagaki
  • Organizer: ENDO2018(米国内分泌学会)
  • Int'l Joint Research
• [Patent(Industrial Property Rights)] ステロイド産生細胞の製造方法 (2017)
  • Inventor(s): 長船健二、曽根正勝、稲垣暢也、中尾一和、松尾浩司
  • Industrial Property Rights Holder: 国立大学法人京都大学
  • Industrial Property Rights Type: 特許
  • Filing Date: 2017