Lineage fate of ductular reactions in liver injury and carcinogenesis
Simone Jörs, Petia Jeliazkova, Marc Ringelhan, Julian Thalhammer, Stephanie Dürl, Jorge Ferrer, Maike Sander, Mathias Heikenwalder, Roland M. Schmid, Jens T. Siveke, Fabian Geisler
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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Research Article Hepatology

Lineage fate of ductular reactions in liver injury and carcinogenesis

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 5

DRCs do not give rise to tumors in selected mouse HCC models.

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DRCs do not give rise to tumors in selected mouse HCC models. (A) R26Tom...
(A) R26Tom Hnf1b-CreER animals (tamoxifen at P10) were injected with DEN (25 mg/kg BW) and analyzed at 10 to 12 months after DEN treatment (n = 6). Representative IHC micrographs of serial sections obtained from one DEN-induced tumor nodule stained for collagen IV (Col IV), Ki67, GP73, or AFP. Representative macroscopic transmitted light and fluorescent whole-liver images from one DEN-treated animal show all nodular lesions (encircled by dashed lines) negative for tdTom. Co-IF analysis for tdTom and collagen IV revealed sporadic tdTom+ DRCs (asterisks) at the tumor margins and within the tumor nodules, but tumor cells never costained for tdTom (tumor nodules obtained from different animals are encircled by dashed lines; insets are shown at higher magnification below). (B) Likewise, characterization of tumors observed in Mdr2–/– R26Tom Hnf1b-CreER animals (tamoxifen at P21) was performed by IHC for collagen IV, Ki67, GP73, and AFP in 12-month-old animals; nodule formation was observed in 4 out of n = 6 animals. Representative serial cryosections of tumor nodules processed from different mice for H&E and co-IF for tdTom and collagen IV indicate tumor cells negative for tdTom (encircled by dashed lines). tdTom+ DRCs (asterisks) are typically observed outside tumor margins and rarely found within. Tu, tumor. Scale bar: 1,000 μm (low-magnification H&E, top panel, B); 500 μm (H&E mouse 1–3, B); 100 μm (low-magnification H&E, IHC, and top row IF, A; high-magnification H&E, IHC, and top row IF, B); 20 μm (high-magnification H&E and bottom row IF, A; bottom row IF, B).