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 journalArticle

12 Citations (Scopus)

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 languageEnglish
Pages (from-to)306-316
Number of pages11
JournalStem Cell Reports
Volume11
Issue number2
DOIs
Publication statusPublished - Aug 14 2018
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Genetics
  • Developmental Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'Optimal Hypoxia Regulates Human iPSC-Derived Liver Bud Differentiation through Intercellular TGFB Signaling'. Together they form a unique fingerprint.

Cite this