Significance of dopamine D1 receptor signalling for steroidogenic differentiation of human induced pluripotent stem cells

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

doi:10.1038/s41598-017-15485-4

Significance of dopamine D₁ receptor signalling for steroidogenic differentiation of human induced pluripotent stem cells

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

Research output: Contribution to journal › Article › peer-review

6 Citations (Scopus)

Abstract

Human induced pluripotent stem cells (hiPSCs) are expected to be both a revolutionary cell source for regenerative medicine and a powerful tool to investigate the molecular mechanisms underlying human cell development in vitro. In the present study, 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 Odd-skipped related 1 (OSR1), an early IM marker. We identified cabergoline as an inducer of 3β-hydroxysteroid dehydrogenase, an essential enzyme for adrenogonadal 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 by increasing intracellular cyclic AMP. Further analysis of OSR1⁺ cells transfected with steroidogenic factor-1/adrenal 4 binding protein revealed that D₁ receptor agonist upregulated expression of various steroidogenic enzymes and increased secretion of steroid hormones synergistically with adrenocorticotropic hormone. These results suggest the importance of dopamine D₁ receptor signalling in steroidogenic differentiation, which contributes to effective induction of steroidogenic cells from hiPSCs.

Original language	English
Article number	15120
Journal	Scientific reports
Volume	7
Issue number	1
DOIs	https://doi.org/10.1038/s41598-017-15485-4
Publication status	Published - 2017 Dec 1
Externally published	Yes

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41598-017-15485-4

Cite this

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. (2017). Significance of dopamine D₁ receptor signalling for steroidogenic differentiation of human induced pluripotent stem cells. Scientific reports, 7(1), [15120]. https://doi.org/10.1038/s41598-017-15485-4

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 2017, 'Significance of dopamine D₁ receptor signalling for steroidogenic differentiation of human induced pluripotent stem cells', Scientific reports, vol. 7, no. 1, 15120. https://doi.org/10.1038/s41598-017-15485-4

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title = "Significance of dopamine D1 receptor signalling for steroidogenic differentiation of human induced pluripotent stem cells",

abstract = "Human induced pluripotent stem cells (hiPSCs) are expected to be both a revolutionary cell source for regenerative medicine and a powerful tool to investigate the molecular mechanisms underlying human cell development in vitro. In the present study, 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 Odd-skipped related 1 (OSR1), an early IM marker. We identified cabergoline as an inducer of 3β-hydroxysteroid dehydrogenase, an essential enzyme for adrenogonadal 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 by increasing intracellular cyclic AMP. Further analysis of OSR1+ cells transfected with steroidogenic factor-1/adrenal 4 binding protein revealed that D1 receptor agonist upregulated expression of various steroidogenic enzymes and increased secretion of steroid hormones synergistically with adrenocorticotropic hormone. These results suggest the importance of dopamine D1 receptor signalling in steroidogenic differentiation, which contributes to effective induction of steroidogenic cells from hiPSCs.",

author = "Koji Matsuo and Masakatsu Sone and Kyoko Honda-Kohmo and Takafumi Toyohara and Takuhiro Sonoyama and Daisuke Taura and Katsutoshi Kojima and Yorihide Fukuda and Youichi Ohno and Mayumi Inoue and Akira Ohta and Kenji Osafune and Kazuwa Nakao and Nobuya Inagaki",

note = "Funding Information: We thank Ms. Yoshie Fukuchi for technical assistance and the members of Dr. Osafune{\textquoteright}s laboratory for their valuable help. This work was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology (Japan, JSPS KAKENHI Grant number 26461380, 17K09880). Publisher Copyright: {\textcopyright} 2017 The Author(s).",

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AU - Sone, Masakatsu

AU - Honda-Kohmo, Kyoko

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AU - Sonoyama, Takuhiro

AU - Taura, Daisuke

AU - Kojima, Katsutoshi

AU - Fukuda, Yorihide

AU - Ohno, Youichi

AU - Inoue, Mayumi

AU - Ohta, Akira

AU - Osafune, Kenji

AU - Nakao, Kazuwa

AU - Inagaki, Nobuya

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PY - 2017/12/1

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N2 - Human induced pluripotent stem cells (hiPSCs) are expected to be both a revolutionary cell source for regenerative medicine and a powerful tool to investigate the molecular mechanisms underlying human cell development in vitro. In the present study, 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 Odd-skipped related 1 (OSR1), an early IM marker. We identified cabergoline as an inducer of 3β-hydroxysteroid dehydrogenase, an essential enzyme for adrenogonadal 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 by increasing intracellular cyclic AMP. Further analysis of OSR1+ cells transfected with steroidogenic factor-1/adrenal 4 binding protein revealed that D1 receptor agonist upregulated expression of various steroidogenic enzymes and increased secretion of steroid hormones synergistically with adrenocorticotropic hormone. These results suggest the importance of dopamine D1 receptor signalling in steroidogenic differentiation, which contributes to effective induction of steroidogenic cells from hiPSCs.

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