Endothelial cells instruct liver specification of embryonic stem cell-derived endoderm through endothelial VEGFR2 signaling and endoderm epigenetic modifications - ScienceDirect

Stem Cell Research

Songyan Han¹ 

关键词: Mouse embryonic stem cells;    Endoderm hepatic specification;    Endothelial cells;    VEGFR2;    Epigenetic modifications;    ESC;    human embryonic stem cell;    EB;    embryoid body;    AL End;    mouse ESC-derived endoderm cells cultured alone;    CC End;    mouse ESC-derived endoderm cells co-cultured with D4T endothelial cells;    FACS;    fluorescence-activated cell sorting;    AFP;    alpha fetoprotein;    ALB;    albumin;    TTR;    transthyretin;    VPA;    valproic acid;    5-aza;    5-Aza-2′-deoxycytidine;    GSK126;    S-adenosyl-methionine-competitive small molecule inhibitor of EZH2 methyltransferase activity;    DNMT;    DNA methyltransferases;    HMT;    histone methyltransferases;    HAT;    histone acetyltransferase;    HDAC;    histone deacetyltransferases;   

DOI  :  10.1016/j.scr.2018.06.004

学科分类：生物科学（综合）

来源: Elsevier

【 摘 要 】

Liver organogenesis requires complex cell-cell interactions between hepatic endoderm cells and adjacent cell niches. Endothelial cells are key players for endoderm hepatic fate decision. We previously demonstrated that the endothelial cell niche promotes hepatic specification of mouse embryonic stem cell(ESC)-derived endoderm through dual repression of Wnt and Notch pathways in endoderm cells. In the present study, we dissected further the mechanisms by which endothelial cells trigger endoderm hepatic specification. Using our previously established in vitro mouse ESC system mimicking the early hepatic specification process, endoderm cells were purified and co-cultured with endothelial cells to induce hepatic specification. The comparison of transcriptome profiles between hepatic endoderm cells isolated from co-cultures and endoderm cells cultured alone revealed that VEGF signaling instructs hepatic specification of endoderm cells through endothelial VEGFR2 activation. Additionally, epigenetic mark inhibition assays upon co-cultures uncovered that histone acetylation and DNA methylation promote hepatic specification while histone methylation inhibits it. This study provides an efficient 2D platform modelling the endothelial cell niche crosstalk with endoderm, and reveals mechanisms by which endothelial cells promote hepatic specification of mouse ESC-derived endoderm cells through endothelial VEGFR2 activation and endoderm epigenetic modifications.

【 授权许可】

Unknown