Optimal Hypoxia Regulates Human iPSC-Derived Liver Bud Differentiation through Intercellular TGFB Signaling

Hiroaki Ayabe; Takahisa Anada; Takuo Kamoya; Tomoya Sato; Masaki Kimura; Emi Yoshizawa; Shunyuu Kikuchi; Yasuharu Ueno; Keisuke Sekine; J. Gray Camp; Barbara Treutlein; Autumn Ferguson; Osamu Suzuki; Takanori Takebe; Hideki Taniguchi

doi:10.1016/j.stemcr.2018.06.015

Optimal Hypoxia Regulates Human iPSC-Derived Liver Bud Differentiation through Intercellular TGFB Signaling

Hiroaki Ayabe, Takahisa Anada, Takuo Kamoya, Tomoya Sato, Masaki Kimura, Emi Yoshizawa, Shunyuu Kikuchi, Yasuharu Ueno, Keisuke Sekine, J. Gray Camp, Barbara Treutlein, Autumn Ferguson, Osamu Suzuki, Takanori Takebe, Hideki Taniguchi

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

35 Scopus citations

Abstract

Timely controlled oxygen (O ₂ ) delivery is crucial for the developing liver. However, the influence of O ₂ on intercellular communication during hepatogenesis is unclear. Using a human induced pluripotent stem cell-derived liver bud (hiPSC-LB) model, we found hypoxia induced with an O ₂ -permeable plate promoted hepatic differentiation accompanied by TGFB1 and TGFB3 suppression. Conversely, extensive hypoxia generated with an O ₂ -non-permeable plate elevated TGFBs and cholangiocyte marker expression. Single-cell RNA sequencing revealed that TGFB1 and TGFB3 are primarily expressed in the human liver mesenchyme and endothelium similar to in the hiPSC-LBs. Stromal cell-specific RNA interferences indicated the importance of TGFB signaling for hepatocytic differentiation in hiPSC-LB. Consistently, during mouse liver development, the Hif1a-mediated developmental hypoxic response is positively correlated with TGFB1 expression. These data provide insights into the mechanism that hypoxia-stimulated signals in mesenchyme and endothelium, likely through TGFB1, promote hepatoblast differentiation prior to fetal circulation establishment. To delineate the influence of O ₂ on liver development, human induced pluripotent stem cell-derived liver buds were used as a fetal liver model. This model provides insight into hypoxic modulation of mesenchyme-derived TGFB signals that promote hepatoblast differentiation in developing liver buds prior to blood circulation.

Original language	English
Pages (from-to)	306-316
Number of pages	11
Journal	Stem Cell Reports
Volume	11
Issue number	2
DOIs	https://doi.org/10.1016/j.stemcr.2018.06.015
State	Published - 14 Aug 2018
Externally published	Yes

Keywords

differentiation
hypoxia
iPSC
liver bud
organogenesis
organoid
oxygen

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10.1016/j.stemcr.2018.06.015

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Ayabe, H., Anada, T., Kamoya, T., Sato, T., Kimura, M., Yoshizawa, E., Kikuchi, S., Ueno, Y., Sekine, K., Camp, J. G., Treutlein, B., Ferguson, A., Suzuki, O., Takebe, T., & Taniguchi, H. (2018). Optimal Hypoxia Regulates Human iPSC-Derived Liver Bud Differentiation through Intercellular TGFB Signaling. Stem Cell Reports, 11(2), 306-316. https://doi.org/10.1016/j.stemcr.2018.06.015

@article{96e5d7746c3a47ba9aa9b9831afc511e,

title = "Optimal Hypoxia Regulates Human iPSC-Derived Liver Bud Differentiation through Intercellular TGFB Signaling",

abstract = " Timely controlled oxygen (O 2 ) delivery is crucial for the developing liver. However, the influence of O 2 on intercellular communication during hepatogenesis is unclear. Using a human induced pluripotent stem cell-derived liver bud (hiPSC-LB) model, we found hypoxia induced with an O 2 -permeable plate promoted hepatic differentiation accompanied by TGFB1 and TGFB3 suppression. Conversely, extensive hypoxia generated with an O 2 -non-permeable plate elevated TGFBs and cholangiocyte marker expression. Single-cell RNA sequencing revealed that TGFB1 and TGFB3 are primarily expressed in the human liver mesenchyme and endothelium similar to in the hiPSC-LBs. Stromal cell-specific RNA interferences indicated the importance of TGFB signaling for hepatocytic differentiation in hiPSC-LB. Consistently, during mouse liver development, the Hif1a-mediated developmental hypoxic response is positively correlated with TGFB1 expression. These data provide insights into the mechanism that hypoxia-stimulated signals in mesenchyme and endothelium, likely through TGFB1, promote hepatoblast differentiation prior to fetal circulation establishment. To delineate the influence of O 2 on liver development, human induced pluripotent stem cell-derived liver buds were used as a fetal liver model. This model provides insight into hypoxic modulation of mesenchyme-derived TGFB signals that promote hepatoblast differentiation in developing liver buds prior to blood circulation.",

keywords = "differentiation, hypoxia, iPSC, liver bud, organogenesis, organoid, oxygen",

author = "Hiroaki Ayabe and Takahisa Anada and Takuo Kamoya and Tomoya Sato and Masaki Kimura and Emi Yoshizawa and Shunyuu Kikuchi and Yasuharu Ueno and Keisuke Sekine and Camp, {J. Gray} and Barbara Treutlein and Autumn Ferguson and Osamu Suzuki and Takanori Takebe and Hideki Taniguchi",

note = "Publisher Copyright: {\textcopyright} 2018 The Authors",

year = "2018",

month = aug,

day = "14",

doi = "10.1016/j.stemcr.2018.06.015",

language = "English",

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Ayabe, H, Anada, T, Kamoya, T, Sato, T, Kimura, M, Yoshizawa, E, Kikuchi, S, Ueno, Y, Sekine, K, Camp, JG, Treutlein, B, Ferguson, A, Suzuki, O, Takebe, T & Taniguchi, H 2018, 'Optimal Hypoxia Regulates Human iPSC-Derived Liver Bud Differentiation through Intercellular TGFB Signaling', Stem Cell Reports, vol. 11, no. 2, pp. 306-316. https://doi.org/10.1016/j.stemcr.2018.06.015

TY - JOUR

T1 - Optimal Hypoxia Regulates Human iPSC-Derived Liver Bud Differentiation through Intercellular TGFB Signaling

AU - Ayabe, Hiroaki

AU - Anada, Takahisa

AU - Kamoya, Takuo

AU - Sato, Tomoya

AU - Kimura, Masaki

AU - Yoshizawa, Emi

AU - Kikuchi, Shunyuu

AU - Ueno, Yasuharu

AU - Sekine, Keisuke

AU - Camp, J. Gray

AU - Treutlein, Barbara

AU - Ferguson, Autumn

AU - Suzuki, Osamu

AU - Takebe, Takanori

AU - Taniguchi, Hideki

PY - 2018/8/14

Y1 - 2018/8/14

N2 - Timely controlled oxygen (O 2 ) delivery is crucial for the developing liver. However, the influence of O 2 on intercellular communication during hepatogenesis is unclear. Using a human induced pluripotent stem cell-derived liver bud (hiPSC-LB) model, we found hypoxia induced with an O 2 -permeable plate promoted hepatic differentiation accompanied by TGFB1 and TGFB3 suppression. Conversely, extensive hypoxia generated with an O 2 -non-permeable plate elevated TGFBs and cholangiocyte marker expression. Single-cell RNA sequencing revealed that TGFB1 and TGFB3 are primarily expressed in the human liver mesenchyme and endothelium similar to in the hiPSC-LBs. Stromal cell-specific RNA interferences indicated the importance of TGFB signaling for hepatocytic differentiation in hiPSC-LB. Consistently, during mouse liver development, the Hif1a-mediated developmental hypoxic response is positively correlated with TGFB1 expression. These data provide insights into the mechanism that hypoxia-stimulated signals in mesenchyme and endothelium, likely through TGFB1, promote hepatoblast differentiation prior to fetal circulation establishment. To delineate the influence of O 2 on liver development, human induced pluripotent stem cell-derived liver buds were used as a fetal liver model. This model provides insight into hypoxic modulation of mesenchyme-derived TGFB signals that promote hepatoblast differentiation in developing liver buds prior to blood circulation.

AB - Timely controlled oxygen (O 2 ) delivery is crucial for the developing liver. However, the influence of O 2 on intercellular communication during hepatogenesis is unclear. Using a human induced pluripotent stem cell-derived liver bud (hiPSC-LB) model, we found hypoxia induced with an O 2 -permeable plate promoted hepatic differentiation accompanied by TGFB1 and TGFB3 suppression. Conversely, extensive hypoxia generated with an O 2 -non-permeable plate elevated TGFBs and cholangiocyte marker expression. Single-cell RNA sequencing revealed that TGFB1 and TGFB3 are primarily expressed in the human liver mesenchyme and endothelium similar to in the hiPSC-LBs. Stromal cell-specific RNA interferences indicated the importance of TGFB signaling for hepatocytic differentiation in hiPSC-LB. Consistently, during mouse liver development, the Hif1a-mediated developmental hypoxic response is positively correlated with TGFB1 expression. These data provide insights into the mechanism that hypoxia-stimulated signals in mesenchyme and endothelium, likely through TGFB1, promote hepatoblast differentiation prior to fetal circulation establishment. To delineate the influence of O 2 on liver development, human induced pluripotent stem cell-derived liver buds were used as a fetal liver model. This model provides insight into hypoxic modulation of mesenchyme-derived TGFB signals that promote hepatoblast differentiation in developing liver buds prior to blood circulation.

KW - differentiation

KW - hypoxia

KW - iPSC

KW - liver bud

KW - organogenesis

KW - organoid

KW - oxygen

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U2 - 10.1016/j.stemcr.2018.06.015

DO - 10.1016/j.stemcr.2018.06.015

M3 - Article

C2 - 30033085

AN - SCOPUS:85053359101

SN - 2213-6711

VL - 11

SP - 306

EP - 316

JO - Stem Cell Reports

JF - Stem Cell Reports

IS - 2

ER -

Optimal Hypoxia Regulates Human iPSC-Derived Liver Bud Differentiation through Intercellular TGFB Signaling

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Keywords

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