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

被引：35

作者：

Ayabe, Hiroaki ^{[1
]}

Anada, Takahisa ^{[2
]}

Kamoya, Takuo ^{[2
]}

Sato, Tomoya ^{[2
]}

Kimura, Masaki ^{[4
]}

Yoshizawa, Emi ^{[1
]}

Kikuchi, Shunyuu ^{[1
]}

Ueno, Yasuharu ^{[1
]}

Sekine, Keisuke ^{[1
]}

Camp, J. Gray ^{[3
]}

Treutlein, Barbara ^{[3
]}

Ferguson, Autumn ^{[4
]}

Suzuki, Osamu ^{[2
]}

Takebe, Takanori ^{[1
,4
,5
,6
]}

Taniguchi, Hideki ^{[1
]}

机构：

[1] Yokohama City Univ, Grad Sch Med, Dept Regenerat Med, Kanazawa Ku 3-9, Yokohama, Kanagawa 2360004, Japan

[2] Tohoku Univ, Grad Sch Dent, Div Craniofacial Funct Engn, Aoba Ku, 4-1 Seiryo Machi, Sendai, Miyagi 9808575, Japan

[3] Max Planck Inst Evolutionary Anthropol, D-04103 Leipzig, Germany

[4] Cincinnati Childrens Hosp Med Ctr, Ctr Stem Cell & Organoid Med CuSTOM, Div Gastroenterol Hepatol & Nutr, Dev Biol, 3333 Burnet Ave, Cincinnati, OH 45229 USA

[5] Univ Cincinnati, Dept Pediat, Coll Med, 3333 Burnet Ave, Cincinnati, OH 45229 USA

[6] Tokyo Med & Dent Univ, Inst Res, Bunkyo Ku, 1-5-45 Yushima, Tokyo 1138510, Japan

来源：

STEM CELL REPORTS | 2018年 / 11卷 / 02期

基金：

日本科学技术振兴机构;

关键词：

PLURIPOTENT STEM-CELLS; TRANSCRIPTION FACTORS; BETA; EXPRESSION; TGF-BETA-1; SYSTEM; PROLIFERATION; INHIBITION; MATURATION; APOPTOSIS;

D O I：

10.1016/j.stemcr.2018.06.015

中图分类号：

Q813 [细胞工程];

学科分类号：

摘要：

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 Hifla-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.

引用

页码：306 / 316

页数：11

共 33 条

[1] Evaluation of bioactivity of octacalcium phosphate using osteoblastic cell aggregates on a spheroid culture device [J].