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Lineage fate of ductular reactions in liver injury and carcinogenesis
Simone Jörs, … , Jens T. Siveke, Fabian Geisler
Simone Jörs, … , Jens T. Siveke, Fabian Geisler
Published April 27, 2015
Citation Information: J Clin Invest. 2015;125(6):2445-2457. https://doi.org/10.1172/JCI78585.
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Research Article Hepatology

Lineage fate of ductular reactions in liver injury and carcinogenesis

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Abstract

Ductular reactions (DRs) are observed in virtually all forms of human liver disease; however, the histogenesis and function of DRs in liver injury are not entirely understood. It is widely believed that DRs contain bipotential liver progenitor cells (LPCs) that serve as an emergency cell pool to regenerate both cholangiocytes and hepatocytes and may eventually give rise to hepatocellular carcinoma (HCC). Here, we used a murine model that allows highly efficient and specific lineage labeling of the biliary compartment to analyze the histogenesis of DRs and their potential contribution to liver regeneration and carcinogenesis. In multiple experimental and genetic liver injury models, biliary cells were the predominant precursors of DRs but lacked substantial capacity to produce new hepatocytes, even when liver injuries were prolonged up to 12 months. Genetic modulation of NOTCH and/or WNT/β-catenin signaling within lineage-tagged DRs impaired DR expansion but failed to redirect DRs from biliary differentiation toward the hepatocyte lineage. Further, lineage-labeled DRs did not produce tumors in genetic and chemical HCC mouse models. In summary, we found no evidence in our system to support mouse biliary-derived DRs as an LPC pool to replenish hepatocytes in a quantitatively relevant way in injury or evidence that DRs give rise to HCCs.

Authors

Simone Jörs, Petia Jeliazkova, Marc Ringelhan, Julian Thalhammer, Stephanie Dürl, Jorge Ferrer, Maike Sander, Mathias Heikenwalder, Roland M. Schmid, Jens T. Siveke, Fabian Geisler

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Figure 4

DDC-induced DRs do not escape their biliary fate after genetic ablation of NOTCH and/or activation of WNT/β-catenin signaling.

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DDC-induced DRs do not escape their biliary fate after genetic ablation ...
(A) For HNF1β compartment-specific genetic deletion of the NOTCH-adaptor protein RBP-Jκ and/or stable expression of the WNT effector β-catenin, R26Tom Rbpjfl/fl Hnf1b-CreER (n = 8), R26Tom CatnbΔex3 Hnf1b-CreER (n = 5), and R26Tom CatnbΔex3 Rbpjfl/fl Hnf1b-CreER (n = 4) animals were injected with tamoxifen (i.p., 100 μg/g BW at week 5) and subjected to 2 weeks of DDC diet (week 6–8). Equally treated R26Tom Hnf1b-CreER animals (n = 8) served as controls. Representative co-IF images for tdTom, tdTom/CK19, tdTom/Ki67, and tdTom/acetylated tubulin are shown that demonstrate reduced proliferative expansion and impaired biliary maturation of tdTom+ DRCs after both NOTCH inactivation and/or WNT/ β-catenin activation (arrows indicate tdTom+ DRCs that coexpress Ki67 or acetylated tubulin). In all models, DRCs failed to undergo lineage conversion to hepatocytes, as assessed by tdTom/HNF4α co-IF analysis. (B) Quantification of co-IF data (mean value ± SEM expressed in percentage; *P < 0.05, **P < 0.01, ***P < 0.001 [1-way ANOVA followed by Tukey’s post-test]). Scale bar: 100 μm (first column); 20 μm (second through fifth columns).
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