Inflammatory Cytokine TNFα Promotes the Long-Term Expansion of Primary Hepatocytes in 3D Culture

In the healthy adult liver, most hepatocytes proliferate minimally. However, upon physical or chemical injury to the liver, hepatocytes proliferate extensively in vivo under the direction of multiple extracellular cues, including Wnt and pro-inflammatory signals. Currently, liver organoids can be ge...

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Bibliographic Details
Published in:Cell 2018-11, Vol.175 (6), p.1607-1619.e15
Main Authors: Peng, Weng Chuan, Logan, Catriona Y., Fish, Matt, Anbarchian, Teni, Aguisanda, Francis, Álvarez-Varela, Adrián, Wu, Peng, Jin, Yinhua, Zhu, Junjie, Li, Bin, Grompe, Markus, Wang, Bruce, Nusse, Roel
Format: Article
Language:English
Subjects:
3D culture
Animals
Antigens, Differentiation - biosynthesis
Cell Culture Techniques
Cell Line, Transformed
Cell Proliferation - drug effects
Hep G2 Cells
hepatocyte
Hepatocytes - metabolism
Hepatocytes - transplantation
Human Umbilical Vein Endothelial Cells
Humans
inflammatory cytokine
injury
liver
Liver - injuries
Liver - metabolism
Mice, Knockout
organoid
regeneration
Spheroids, Cellular - metabolism
Spheroids, Cellular - transplantation
Time Factors
TNFα
Tumor Necrosis Factor-alpha - pharmacology
Wnt
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Summary:In the healthy adult liver, most hepatocytes proliferate minimally. However, upon physical or chemical injury to the liver, hepatocytes proliferate extensively in vivo under the direction of multiple extracellular cues, including Wnt and pro-inflammatory signals. Currently, liver organoids can be generated readily in vitro from bile-duct epithelial cells, but not hepatocytes. Here, we show that TNFα, an injury-induced inflammatory cytokine, promotes the expansion of hepatocytes in 3D culture and enables serial passaging and long-term culture for more than 6 months. Single-cell RNA sequencing reveals broad expression of hepatocyte markers. Strikingly, in vitro-expanded hepatocytes engrafted, and significantly repopulated, the injured livers of Fah−/− mice. We anticipate that tissue repair signals can be harnessed to promote the expansion of otherwise hard-to-culture cell-types, with broad implications. [Display omitted] •Inflammatory cytokine TNFα promotes long-term expansion of primary hepatocytes•3D hepatocytes broadly express hepatocyte but not biliary markers•3D hepatocytes engraft and extensively repopulate the injured livers of Fah−/− mice•Insights into tissue repair signals for the expansion of other primary cell types The inflammatory cytokine TNFα enables the establishment of long-term 3D mouse organoid cultures from hepatocytes that are able to successfully engraft and repopulate damaged mouse livers.
ISSN:0092-8674
1097-4172
DOI:10.1016/j.cell.2018.11.012