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

Akihiro Asai, Eitaro Aihara, Carey Watson, Reena Mourya, Tatsuki Mizuochi, Pranavkumar Shivakumar, Kieran Phelan, Christopher Mayhew, Michael Helmrath, Takanori Takebe, James Wells, Jorge A. Bezerra

Research output: Contribution to journalArticlepeer-review

91 Scopus citations


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 cellto- 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 (HEiPSCs) 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 hepatocytelike 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 selforganization 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.

Original languageEnglish (US)
Pages (from-to)1056-1064
Number of pages9
JournalDevelopment (Cambridge)
Issue number6
StatePublished - Mar 15 2017
Externally publishedYes


  • ABCB11
  • Hepatocyte differentiation
  • Liver development
  • Regeneration
  • Tissue engineering

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology


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