Long-Term Expansion of Functional Mouse and Human Hepatocytes as 3D Organoids
Hu, Huili; Gehart, Helmuth; Artegiani, Benedetta; LÖpez-Iglesias, Carmen; Dekkers, Florijn; Basak, Onur; van Es, Johan; Chuva de Sousa Lopes, Susana M.; Begthel, Harry; Korving, Jeroen; van den Born, Maaike; Zou, Chenhui; Quirk, Corrine; Chiriboga, Luis; Rice, Charles M.; Ma, Stephanie; Rios, Anne; Peters, Peter J.; de Jong, Ype P.; Clevers, Hans
(2018) Cell, volume 175, issue 6, pp. 1591 - 1606.e19
(Article)
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
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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. Modeling the regenerative ability of the liver in response to acute damage using long-term 3D organoid cultures in mice and human cells yields proliferative hepatocytes that are able to successfully engraft in animal models.
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Keywords: Hepatocyte Organoid, Hepatocyte Proliferation, Human Liver Organoid, Liver Regeneration, General Biochemistry,Genetics and Molecular Biology
ISSN: 0092-8674
Publisher: Cell Press
Note: Funding Information: Thanks to Reinier van der Linden, Stefan van der Elst in FACS facility and Anko de Graaff in Imaging Centre (HIC) of Hubrecht Institute; to Judith Vivié and Mauro Muraro in van Oudenaarden group for single-cell sequencing library and mapping; to the Microscopy Core Lab of M4I Nanoscopy in Maastricht University, in particular to Hans Duimel and Nino lakobachvili; and to Inha Heo, Marrit Putker Kai Kretzschmar and Georg Busslinger. We sincerely acknowledge all clinical donors. This research was supported by an MKMD grant ( 114021012 ) from Netherlands Organization for Scientific Research (NWO-ZonMw ), Stichting Vrienden van Hubrecht 2012.10, KNAW 3V-Fund IB/4095 and the Koerber Foundation to H.C.. H.H. was supported by the National Natural Science Foundation of China ( 31501179 ), the Foundation for Outstanding Young Scientist in Shandong Province ( BS2014SW004 ) and Future Scientist Program of Chinese Scholarship Council (CSC ). H.G. was supported by VENI grant from the NWO-ZonMW 016.166.119 . B.A. was supported by fellowship NWO/VENI 863.15.015 . Funding Information: Thanks to Reinier van der Linden, Stefan van der Elst in FACS facility and Anko de Graaff in Imaging Centre (HIC) of Hubrecht Institute; to Judith Vivi? and Mauro Muraro in van Oudenaarden group for single-cell sequencing library and mapping; to the Microscopy Core Lab of M4I Nanoscopy in Maastricht University, in particular to Hans Duimel and Nino lakobachvili; and to Inha Heo, Marrit Putker Kai Kretzschmar and Georg Busslinger. We sincerely acknowledge all clinical donors. This research was supported by an MKMD grant (114021012) from Netherlands Organization for Scientific Research (NWO-ZonMw), Stichting Vrienden van Hubrecht 2012.10, KNAW 3V-Fund IB/4095 and the Koerber Foundation to H.C. H.H. was supported by the National Natural Science Foundation of China (31501179), the Foundation for Outstanding Young Scientist in Shandong Province (BS2014SW004) and Future Scientist Program of Chinese Scholarship Council (CSC). H.G. was supported by VENI grant from the NWO-ZonMW 016.166.119. B.A. was supported by fellowship NWO/VENI 863.15.015. Publisher Copyright: © 2018 Elsevier Inc.
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