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Cell. 2018 Nov 29;175(6):1591-1606.e19. doi: 10.1016/j.cell.2018.11.013.

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

Author information

1
Oncode Institute, Hubrecht Institute, KNAW (Royal Netherlands Academy of Arts and Sciences), Utrecht, the Netherlands; The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Genetics, School of Basic Medical Sciences, Shandong University, 250012 Jinan, China.
2
Oncode Institute, Hubrecht Institute, KNAW (Royal Netherlands Academy of Arts and Sciences), Utrecht, the Netherlands.
3
The Maastricht Multimodal Molecular Imaging Institute, Maastricht University, 6229 ER Maastricht, the Netherlands.
4
Anatomy and Embryology, Leiden University Medical Center, Einthovenweg, 2333 ZC Leiden, the Netherlands.
5
Division of Gastroenterology and Hepatology, Weill Cornell Medicine, New York, NY10065, USA; Laboratory of Virology and Infectious Disease, the Rockefeller University, New York, NY 10065, USA.
6
Laboratory of Virology and Infectious Disease, the Rockefeller University, New York, NY 10065, USA.
7
Department of Pathology, NYU Medical Center, New York, NY10003, USA.
8
School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong.
9
The Princess Maxima Center for Pediatric Oncology, Utrecht, the Netherlands.
10
Oncode Institute, Hubrecht Institute, KNAW (Royal Netherlands Academy of Arts and Sciences), Utrecht, the Netherlands; University Medical Center Utrecht, Cancer Genomics Netherlands, 3584CX Utrecht, the Netherlands; The Princess Maxima Center for Pediatric Oncology, Utrecht, the Netherlands. Electronic address: h.clevers@hubrecht.eu.

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 from cholangiocytes, the hepatocyte proliferative response has not been recapitulated in culture. Here, we describe the establishment of a long-term 3D organoid 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.

KEYWORDS:

Hepatocyte Organoid; Hepatocyte Proliferation; Human Liver Organoid; Liver Regeneration

PMID:
30500538
DOI:
10.1016/j.cell.2018.11.013

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