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

Weng Chuan Peng, Catriona Y. Logan, Matt Fish, Teni Anbarchian, Francis Aguisanda, Adrián Álvarez-Varela, Peng Wu, Yinhua Jin, Junjie Zhu, Bin Li, Markus Grompe, Bruce Wang, Roel Nusse

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

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. 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.

Original languageEnglish (US)
Pages (from-to)1607-1619.e15
JournalCell
Volume175
Issue number6
DOIs
StatePublished - Nov 29 2018

Keywords

  • 3D culture
  • hepatocyte
  • inflammatory cytokine
  • injury
  • liver
  • organoid
  • regeneration
  • TNFα
  • Wnt

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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  • Cite this

    Peng, W. C., Logan, C. Y., Fish, M., Anbarchian, T., Aguisanda, F., Álvarez-Varela, A., Wu, P., Jin, Y., Zhu, J., Li, B., Grompe, M., Wang, B., & Nusse, R. (2018). Inflammatory Cytokine TNFα Promotes the Long-Term Expansion of Primary Hepatocytes in 3D Culture. Cell, 175(6), 1607-1619.e15. https://doi.org/10.1016/j.cell.2018.11.012