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Wnt/?-catenin signaling cell-autonomously converts non-hepatic endodermal cells to a liver fate.

ABSTRACT: Wnt/?-catenin signaling plays multiple roles in liver development including hepatoblast proliferation and differentiation, hepatocyte differentiation, and liver zonation. A positive role for Wnt/?-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/?-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/?-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/?-catenin signaling upon heat-shock, we show that Wnt/?-catenin signaling acts cell-autonomously in endodermal cells to induce hepatic conversion. Altogether, these data demonstrate that Wnt/?-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.

SUBMITTER: So J

PROVIDER: S-EPMC3545266 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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Wnt/β-catenin signaling cell-autonomously converts non-hepatic endodermal cells to a liver fate.

So Juhoon J Martin Benjamin L BL Kimelman David D Shin Donghun D

Biology open 20120714 1

Wnt/β-catenin signaling plays multiple roles in liver development including hepatoblast proliferation and differentiation, hepatocyte differentiation, and liver zonation. A positive role for Wnt/β-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/β-catenin signaling regulates liver specification. First, using lineage tracing we show that ectopic hepatoblasts ...[more]

PMID: 23336074

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Project description:BackgroundThe zebrafish retina maintains two populations of stem cells: first, the germinal zone or ciliary marginal zone (CMZ) contains multipotent retinal progenitors that add cells to the retinal periphery as the fish continue to grow; second, radial glia (Müller cells) occasionally divide asymmetrically to generate committed progenitors that differentiate into rod photoreceptors, which are added interstitially throughout the retina with growth. Retinal injury stimulates Müller glia to dedifferentiate, re-enter the cell cycle, and generate multipotent retinal progenitors similar to those in the CMZ to replace missing neurons. The specific signals that maintain these two distinct populations of endogenous retinal stem cells are not understood.ResultsWe used genetic and pharmacological manipulation of the ?-catenin/Wnt signaling pathway to show that it is required to maintain proliferation in the CMZ and that hyperstimulation of ?-catenin/Wnt signaling inhibits normal retinal differentiation and expands the population of proliferative retinal progenitors. To test whether similar effects occur during regeneration, we developed a method for making rapid, selective photoreceptor ablations in larval zebrafish with intense light. We found that dephosphorylated ?-catenin accumulates in Müller glia as they re-enter the cell cycle following injury, but not in Müller glia that remain quiescent. Activation of Wnt signaling is required for regenerative proliferation, and hyperstimulation results in loss of Müller glia from the INL as all proliferative cells move into the ONL.Conclusions?-catenin/Wnt signaling is thus required for the maintenance of retinal progenitors during both initial development and lesion-induced regeneration, and is sufficient to prevent differentiation of those progenitors and maintain them in a proliferative state. This suggests that the ?-catenin/Wnt cascade is part of the shared molecular circuitry that maintains retinal stem cells for both homeostatic growth and epimorphic regeneration.

Dataset Information

Wnt/?-catenin signaling cell-autonomously converts non-hepatic endodermal cells to a liver fate.

Publications

Wnt/β-catenin signaling cell-autonomously converts non-hepatic endodermal cells to a liver fate.

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