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Paracrine signals regulate human liver organoid maturation from induced pluripotent stem cells

A. Asai,E. Aihara,Carey L. Watson,Reena Mourya,T. Mizuochi,P. Shivakumar,Kieran Phelan,C. Mayhew,M. Helmrath,T. Takebe,James M. Wells,J. Bezerra

Published 2017 in Development

ABSTRACT

ABSTRACT A self-organizing organoid model provides a new approach to study the mechanism of human liver organogenesis. Previous animal models documented that simultaneous paracrine signaling and cell-to-cell surface contact regulate hepatocyte differentiation. To dissect the relative contributions of the paracrine effects, we first established a liver organoid using human induced pluripotent stem cells (iPSCs), mesenchymal stem cells (MSCs) and human umbilical vein endothelial cells (HUVECs) as previously reported. Time-lapse imaging showed that hepatic-specified endoderm iPSCs (HE-iPSCs) self-assembled into three-dimensional organoids, resulting in hepatic gene induction. Progressive differentiation was demonstrated by hepatic protein production after in vivo organoid transplantation. To assess the paracrine contributions, we employed a Transwell system in which HE-iPSCs were separately co-cultured with MSCs and/or HUVECs. Although the three-dimensional structure did not form, their soluble factors induced a hepatocyte-like phenotype in HE-iPSCs, resulting in the expression of bile salt export pump. In conclusion, the mesoderm-derived paracrine signals promote hepatocyte maturation in liver organoids, but organoid self-organization requires cell-to-cell surface contact. Our in vitro model demonstrates a novel approach to identify developmental paracrine signals regulating the differentiation of human hepatocytes. Summary: Paracrine signals from MSCs or HUVECs are able to promote hepatocyte differentiation independently, but both must co-exist to allow for the cell-cell contact and organization into a 3D liver organoid.

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