Format

Send to

Choose Destination
Cell. 2018 Nov 29;175(6):1607-1619.e15. doi: 10.1016/j.cell.2018.11.012.

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

Author information

1
Howard Hughes Medical Institute, Department of Developmental Biology, Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: wcpeng@stanford.edu.
2
Howard Hughes Medical Institute, Department of Developmental Biology, Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
3
Howard Hughes Medical Institute, Department of Developmental Biology, Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA.
4
Department of Electrical Engineering, Stanford University, Stanford, CA 94305, USA.
5
Oregon Stem Cell Center, Oregon Health and Science University, Portland, OR 97239, USA.
6
Department of Medicine and Liver Center, University of California, San Francisco, San Francisco, CA 94143, USA.
7
Howard Hughes Medical Institute, Department of Developmental Biology, Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: rnusse@stanford.edu.

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.

KEYWORDS:

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

PMID:
30500539
DOI:
10.1016/j.cell.2018.11.012

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center