Journal
BIOLOGY OPEN
Volume 2, Issue 1, Pages 30-36Publisher
COMPANY OF BIOLOGISTS LTD
DOI: 10.1242/bio.20122857
Keywords
Hepatoblast; Liver specification; Hepatic conversion; Endoderm; Zebrafish; Fate-change
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Funding
- American Liver Foundation
- UPMC Competitive Medical Research Fund
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Wnt/beta-catenin signaling plays multiple roles in liver development including hepatoblast proliferation and differentiation, hepatocyte differentiation, and liver zonation. A positive role for Wnt/beta-catenin signaling in liver specification was recently identified in zebrafish; however, its underlying cellular mechanisms are unknown. Here, we present two cellular mechanisms by which Wnt/beta-catenin signaling regulates liver specification. First, using lineage tracing we show that ectopic hepatoblasts, which form in the endoderm posterior to the liver upon activation of Wnt/beta-catenin signaling, are derived from the direct conversion of non-hepatic endodermal cells, but not from the posterior migration of hepatoblasts. We found that endodermal cells at the 4-6 th somite levels, which normally give rise to the intestinal bulb or intestine, gave rise to hepatoblasts in Wnt8a-overexpressing embryos, and that the distribution of traced endodermal cells in Wnt8a-overexpressing embryos was similar to that in controls. Second, by using an endoderm-restricted cell-transplantation technique and mosaic analysis with transgenic lines that cell-autonomously suppress or activate Wnt/beta-catenin signaling upon heat-shock, we show that Wnt/beta-catenin signaling acts cell-autonomously in endodermal cells to induce hepatic conversion. Altogether, these data demonstrate that Wnt/beta-catenin signaling can induce the fate-change of non-hepatic endodermal cells into a liver fate in a cell-autonomous manner. These findings have potential application to hepatocyte differentiation protocols for the generation of mature hepatocytes from induced pluripotent stem cells, supplying a sufficient amount of hepatocytes for cell-based therapies to treat patients with severe liver diseases. (C) 2012. Published by The Company of Biologists Ltd.
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