Chemical screening for steroidogenic differentiation of human iPSC-derived intermediate mesoderm cells.

• Project/Area Number: 26461380
• 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)
• Research Collaborator: OSAFUNE Kenji
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2016: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: ステロイドホルモン / 副腎皮質 / 性腺 / 発生分化 / 内分泌 / ステロイド / 再生 / 内分泌学

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. We first performed chemical screening to identify small molecules that induce steroidogenic differentiation of IM cells expressing OSR1, an early IM marker. We identified cabergoline as an inducer of 3β-HSD2, an essential enzyme for steroidogenesis. Although cabergoline is a potent dopamine D2 receptor agonist, additional experiments showed that cabergoline exerted effects as a low-affinity agonist of D1 receptors. Further analysis of OSR1+ cells transfected with SF-1/Ad4BP revealed that D1 receptor agonist upregulated expression of various steroidogenic enzymes and increased secretion of steroid hormones. These results suggest the importance of dopamine D1 receptor signalling in steroidogenic differentiation, which contributes to effective induction of steroidogenic cells from hiPSCs.

Research Products

• [Journal Article] Transcriptional Analysis of Intravenous Immunoglobulin Resistance in Kawasaki Disease Using an Induced Pluripotent Stem Cell Disease Model (2017)
  • Author(s): Ikeda K, Mizoro Y, Ameku T, Nomiya Y, Mae SI, Matsui S, Kuchitsu Y, Suzuki C, Hamaoka-Okamoto A, Yahata T, Sone M, Okita K, Watanabe A, Osafune K, Hamaoka K.
  • Journal Title: Circulation Journal Volume: 81 Issue: 1 Pages: 110-118
  • DOI: 10.1253/circj.CJ-16-0541
  • NAID: 130005252647
  • ISSN: 1346-9843, 1347-4820
  • Peer Reviewed / Open Access
• [Journal Article] Endothelium-derived C-type natriuretic peptide contributes to blood pressure regulation by maintaining endothelial integrity. (2017)
  • Author(s): Nakao K, Kuwahara K, Nishikimi T, Nakagawa Y, Kinoshita H, Minami T, Kuwabara Y, Yamada C, Yamada Y, Tokudome T, Nagai-Okatani C, Minamino N, Nakao YM, Yasuno S, Ueshima K, Sone M, Kimura T, Kangawa K, Nakao K
  • Journal Title: Hypertension. Volume: 69 Issue: 2 Pages: 286-296
  • DOI: 10.1161/hypertensionaha.116.08219
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Crucial role of mesangial cell-derived connective tissue growth factor in a mouse model of anti-glomerular basement membrane glomerulonephritis. (2017)
  • Author(s): Toda N, Mori K, Kasahara M, Ishii A, Koga K, Ohno S, Mori KP. Kato Y, Osaki K, Kuwabara T, Kojima K, Taura D, Sone M, Matsusaka T, Nakao K, Mukoyama M, Yanagita M, Yokoi H.
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 42114-42114
  • DOI: 10.1038/srep42114
  • NAID: 120005997757
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Overall safety and efficacy of high-dose and low-dose intravenous glucocorticoid therapy in patients with moderate-to-severe active Graves’ ophthalmopathy (2016)
  • Author(s): Ueda-Sakane Y, Kanamoto N, Fushimi Y, Tanaka-Mizuno S, Yasuno S, Miura M, Sone M, Yasoda A, Okada T, Togashi K, Nakao K, Inagaki N
  • Journal Title: Endocrine Journal Volume: 63 Issue: 8 Pages: 703-714
  • DOI: 10.1507/endocrj.EJ16-0038
  • NAID: 130005261383
  • ISSN: 0918-8959, 1348-4540
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Identification of MMP1 as a novel risk factor for intracranial aneurysms in ADPKD using iPSC models. (2016)
  • Author(s): Ameku T, Watanabe A, Osafune K et al.
  • Journal Title: Sci Rep. Volume: 6 Issue: 1 Pages: 30013-30013
  • DOI: 10.1038/srep30013
  • NAID: 120005825896
  • Peer Reviewed / Open Access
• [Journal Article] Impaired adipogenic capacity in induced pluripotent stem cells from lipodystrophic patients with BSCL2 mutations (2016)
  • Author(s): 1.E. Mori, J. Fujikura, M. Noguchi, K. Nakao, M. Matsubara, M. Sone, D. Taura, T. Kusakabe, K. Ebihara, T. Tanaka, K. Hosoda, K. Takahashi, I. Asaka, N. Inagaki, K. Nakao
  • Journal Title: Metablism Volume: 65 Issue: 4 Pages: 543-556
  • DOI: 10.1016/j.metabol.2015.12.015
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Role of endogenous ACTH on circadian aldosterone rhythm in patients with primary aldosteronism (2014)
  • Author(s): Sonoyama, T., Sone, M. , Tamura, N., Honda, K., Taura, D., Kojima, K., Fukuda, Y., Kanamoto, N., Miura, M., Yasoda, A., Arai, H., Itoh, H., Nakao, K
  • Journal Title: Endocrine Connections Volume: 3 Issue: 4 Pages: 173-179
  • DOI: 10.1530/ec-14-0086
  • Peer Reviewed / Open Access
• [Presentation] ヒトiPS細胞を用いた副腎皮質分化メカニズムの解明 (2016)
  • Author(s): 松尾浩司、曽根正勝、他
  • Organizer: 第89回日本内分泌学会学術総会
  • Place of Presentation: 京都、日本
  • Year and Date: 2016-04-21
• [Presentation] ヒトiPS細胞を用いた副腎皮質分化メカニズムの解明 (2016)
  • Author(s): 松尾浩司、曽根正勝、他
  • Organizer: 第23回日本ステロイドホルモン学会学術集会
  • Place of Presentation: 倉敷市
  • Year and Date: 2016-01-15
• [Presentation] ヒトiPS／ES 細胞からのステロイド産生細胞分化とケミカルスクリーニング (2015)
  • Author(s): 曽根正勝、他
  • Organizer: 第26回間脳・下垂体・副腎系研究会
  • Place of Presentation: 東京都
  • Year and Date: 2015-03-14
  • Invited
• [Presentation] ヒトiPS細胞のステロイド産生細胞分化系におけるケミカルスクリーニング (2014)
  • Author(s): 本田恭子、曽根正勝、他
  • Organizer: 第87回日本内分泌学会学術総会
  • Place of Presentation: 福岡市
  • Year and Date: 2014-04-25