Multilineage communication regulates human liver bud development from pluripotency

被引：404

作者：

Camp, J. Gray ^{[1
]}

Sekine, Keisuke ^{[2
]}

Gerber, Tobias ^{[1
]}

Loeffler-Wirth, Henry ^{[3
]}

Binder, Hans ^{[3
]}

Gac, Malgorzata ^{[1
]}

Kanton, Sabina ^{[1
]}

Kageyama, Jorge ^{[1
]}

Damm, Georg ^{[4
,5
]}

Seehofer, Daniel ^{[4
,5
]}

Belicova, Lenka ^{[6
]}

Bickle, Marc ^{[6
]}

Barsacchi, Rico ^{[6
]}

Okuda, Ryo ^{[2
]}

Yoshizawa, Emi ^{[2
]}

Kimura, Masaki ^{[2
]}

Ayabe, Hiroaki ^{[2
]}

Taniguchi, Hideki ^{[2
]}

Takebe, Takanori ^{[2
,7
]}

Treutlein, Barbara ^{[1
,6
]}

机构：

[1] Max Planck Inst Evolutionary Anthropol, Dept Evolutionary Genet, Deutsch Pl 6, D-04103 Leipzig, Germany

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

[3] Univ Leipzig, Interdisciplinary Ctr Bioinformat, 16 Hartelstr, D-04107 Leipzig, Germany

[4] Univ Hosp Leipzig, Dept Hepatobiliary & Transplantat Surg, Liebigstr 20, D-04103 Leipzig, Germany

[5] Univ Leipzig, Saxonian Incubator Clin Translat SIKT, 55 Philipp Rosenthal Str, D-04103 Leipzig, Germany

[6] Max Planck Inst Mol Cell Biol & Genet, 108 Pfotenhauerstr, D-01307 Dresden, Germany

[7] Univ Cincinnati, Cincinnati Childrens Hosp Med Ctr, Dept Pediat, 3333 Burnet Ave, Cincinnati, OH 45229 USA

来源：

NATURE | 2017年 / 546卷 / 7659期

基金：

日本科学技术振兴机构;

关键词：

FUNCTIONAL HUMAN LIVER; EXPRESSION; SIGNALS; CELLS; GENERATION; TISSUES;

D O I：

10.1038/nature22796

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Conventional two-dimensional differentiation from pluripotency fails to recapitulate cell interactions occurring during organogenesis. Three-dimensional organoids generate complex organ-like tissues(1); however, it is unclear how heterotypic interactions affect lineage identity. Here we use single-cell RNA sequencing(2,3) to reconstruct hepatocyte-like lineage progression from pluripotency in two-dimensional culture. We then derive three-dimensional liver bud organoids(4) by reconstituting hepatic, stromal, and endothelial interactions, and deconstruct heterogeneity during liver bud development. We find that liver bud hepatoblasts diverge from the two-dimensional lineage, and express epithelial migration signatures characteristic of organ budding. We benchmark three-dimensional liver buds against fetal and adult human liver single-cell RNA sequencing data, and find a striking correspondence between the three-dimensional liver bud and fetal liver cells. We use a receptor-ligand pairing analysis and a high-throughput inhibitor assay to interrogate signalling in liver buds, and show that vascular endothelial growth factor (VEGF) crosstalk potentiates endothelial network formation and hepatoblast differentiation. Our molecular dissection reveals interlineage communication regulating organoid development, and illuminates previously inaccessible aspects of human liver development.

引用

页码：533 / +

页数：22

共 46 条

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