Long-Term Expansion of Functional Mouse and Human Hepatocytes as 3D Organoids

Huili Hu, Helmuth Gehart, Benedetta Artegiani, Carmen Lopez-Iglesias, Florijn Dekkers, Onur Basak, Johan van Es, Susana M. Chuva de Sousa Lopes, Harry Begthel, Jeroen Korving, Maaike van den Born, Chenhui Zou, Corrine Quirk, Luis Chiriboga, Charles M. Rice, Stephanie Ma, Anne Rios, Peter J. Peters, Ype P. de Jong, Hans Clevers*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

The mammalian liver possesses a remarkable regenerative ability. Two modes of damage response have been described: (1) The "oval cell" response emanates from the biliary tree when all hepatocytes are affected by chronic liver disease. (2) A massive, proliferative response of mature hepatocytes occurs upon acute liver damage such as partial hepatectomy (PHx). While the oval cell response has been captured in vitro by growing organoids cholangiocytes, the hepatocyte proliferative response has not been recapitulated in culture. Here, we describe the establishment of a long-term 3D rganoid culture system for mouse and human primary hepatocytes. Organoids can be established from single hepatocytes and grown for multiple months, while retaining key morphological, functional and gene expression features. Transcriptional profiles of the organoids resemble those of proliferating hepatocytes after PHx. Human hepatocyte organoids proliferate extensively after engraftment into mice and thus recapitulate the proliferative damage-response of hepatocytes.

Original languageEnglish
Pages (from-to)1591-1606.e19
Number of pages36
JournalCell
Volume175
Issue number6
DOIs
Publication statusPublished - 29 Nov 2018

Keywords

  • LIVER STEM-CELLS
  • IN-VITRO EXPANSION
  • MATURE HEPATOCYTES
  • SOMATIC MUTATIONS
  • PROGENITOR CELLS
  • ADULT LIVER
  • CULTURE
  • CHOLANGIOCYTES
  • HOMEOSTASIS
  • FIBROBLASTS

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