Biliary epithelial cells are facultative liver stem cells during liver regeneration in adult zebrafish
Isaac M. Oderberg, Wolfram Goessling
Isaac M. Oderberg, Wolfram Goessling
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Research Article Hepatology Stem cells

Biliary epithelial cells are facultative liver stem cells during liver regeneration in adult zebrafish

Abstract

The liver is a highly regenerative organ, yet the presence of a dedicated stem cell population remains controversial. Here, we interrogate a severe hepatocyte injury model in adult zebrafish to define that regeneration involves a stem cell population. After near-total hepatocyte ablation, single-cell transcriptomic and high-resolution imaging analyses throughout the entire regenerative timeline reveal that biliary epithelial cells undergo transcriptional and morphological changes to become hepatocytes. As a population, biliary epithelial cells give rise to both hepatocytes and biliary epithelial cells. Biliary epithelial cells proliferate and dedifferentiate to express hepatoblast transcription factors prior to hepatocyte differentiation. This process is characterized by increased MAPK, PI3K, and mTOR signaling, and chemical inhibition of these pathways impairs biliary epithelial cell proliferation and fate conversion. We conclude that, upon severe hepatocyte ablation in the adult liver, biliary epithelial cells act as facultative liver stem cells in an EGFR-PI3K-mTOR–dependent manner.

Authors

Isaac M. Oderberg, Wolfram Goessling

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Figure 7

Growth factor signaling is elevated during regeneration from hepatocyte ablation.

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Growth factor signaling is elevated during regeneration from hepatocyte ...
(A) Heatmap of the average expression in selected cell states for each gene along the hepatocyte branch. The scaled expression values are average expression values that have been normalized to the minimum and maximum values in each row. The color key from blue to red indicates low to high scaled expression levels, respectively. Two of the earliest growth factors elevated are igfbp1a and hbegfa. (B–D) Immunofluorescence in adult livers showing mCherry (magenta) and pERK (green) (B), Anxa4 (magenta) and pAkt (green) (C), or Anxa4 (magenta) and pS6 (green) (D) signal for animals regenerating from hepatocyte ablation. Time points shown are pERK: mock (n = 9), 0 dpa (n = 7), 1 dpa (n = 8), 2 dpa (n = 8), and 3 dpa (n = 9); pAkt: mock (n = 9), 0 dpa (n = 9), 1 dpa (n = 9), 2 dpa (n = 9), and 3 dpa (n = 9); and pS6: mock (n = 9), 0 dpa (n = 9), 1 dpa (n = 9), 2 dpa (n = 9), and 3 dpa (n = 9). MAPK, PI3K, and mTOR signaling are active during regeneration. Number of animals resembling the representative image are in white in the lower right corner of each image. Scale bars: 50 μm.