Wnt/<i>β</i>‐catenin signalling controls bile duct regeneration by regulating differentiation of ductular reaction cells

Wang, Nan; Kong, Rui; Han, Wei; Lü, Jie

doi:10.1111/jcmm.16017

Cited by 8 publications

(4 citation statements)

References 53 publications

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“…LGR5+ LPC expressed mostly the cholangiocyte marker KRT19 [13]. In line, ductular-reaction cells highly express LGR5 and could differentiate as KRT19 cholangiocytes in Lgr5-CreERT2 mouse model [27]. In contrast, LGR5+ LPC in human cirrhotic livers in our study co-expressed markers for hepatocytes rather than cholangiocytes, even in livers with strong ductular reactions.…”

Section: Discussionsupporting

confidence: 61%

Activated hepatic stellate cells promote expansion of LGR5-positive progenitor cells in fibrotic human liver disease

Kong

Smith-Cortinez

Heegsma

et al. 2023

Preprint

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Background Liver regeneration is compromised in advanced fibrosis or cirrhosis, where progenitor cell therapy is being considered as a therapeutic option. Little is known about the presence and potential role of leucine-rich-repeat-containing G protein-coupled receptor 5-expressing (LGR5+) progenitor cells in chronically injured human liver. In this study, we analyzed LGR5 expression in fibrotic and cirrhotic human livers and studied the interaction between human liver organoids and hepatic stellate cells (HSC) in vitro. Methods Control and fibrotic human liver tissues were combined in a tissue microaarray and sections were stained with H&E or Sirius red, or immune-stained for LGR5 and various liver cell type markers. Adult LGR5+ progenitor cell-derived human liver organoids were co-cultured with human LX-2 HSC or exposed to LX-2 conditioned medium and analyzed by q-PCR and immuno-microscopy. Results LGR5 mRNA were significantly enhanced in fibrotic liver tissue and LGR5+ cell numbers positively correlated with the stage of fibrosis. LGR5+ cells accumulated close to the fibrotic bands and co-expressed hepatocyte markers, but not cholangiocyte markers. TGFβ1-activated LX-2 cells enhanced LGR5 expression in organoids and organoid growth, results that were replicated by exposing organoids to LX-2-conditioned medium. Blocking LX-2 activation by dimethyloxalylglycine prevented all these effects on liver organoids. Conclusion LGR5+ progenitor cells are abundantly present in human liver fibrosis. Activated HSC induce LGR5 expression and growth of human liver organoids. Treatment of advanced liver fibrosis may therefore not strongly benefit from adding exogenous progenitor cells, but rather from promoting expansion and differentiation of the endogenous LGR5+ cells.

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Section: Discussionsupporting

confidence: 61%

Activated hepatic stellate cells promote expansion of LGR5-positive progenitor cells in fibrotic human liver disease

Kong

Smith-Cortinez

Heegsma

et al. 2023

Preprint

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“…Recent findings have shown that progenitor stem‐like cells play a crucial role in biliary epithelium restoration and hepatocyte regeneration 40,41 . As progenitor cells express unique regenerative qualities and seem to be associated with liver tissue fibrosis, they have become an interesting target for the development of novel therapeutic options to tackle biliary injury 42,43 . With K7‐AI model 2.0, DR can be quantified precisely and reproducibly.…”

Section: Discussionmentioning

confidence: 99%

Automated image analysis of keratin 7 staining can predict disease outcome in primary sclerosing cholangitis

Sjöblom

Boyd

Manninen

et al. 2022

Hepatology Research

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Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease that can lead to liver cirrhosis or cholangiocarcinoma. Here, we developed a K7-AI model 2.0 to analyze K7-stained liver specimens of patients with PSC. We found that the K7-AI model 2.0 can serve as a prognostic tool for clinical endpoints, since it was able to provide significant information on disease outcomes based on different histological features.

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“…Particularly, the 3,5‐diethoxycarbonyl‐1,4‐dihydrocollidine (DDC) diet in mice causes bile duct injury and induces ductular reaction cells expressing Leucine‐rich repeat‐containing G‐protein coupled receptor 5 (LGR5) and harboring a bipotent differentiation potential. [ 34 ] Furthermore, the employment of additional chronic injury model also assists in investigating the role of DKK3 in a liver resident stem cell compartment. [ 35 ] Specifically, Dkk3 loss leverages proliferation of hepatocytes and acinar cells after acute injury and attenuates chronic liver damage by expansion of the LGR5‐positive liver progenitor pool.…”

Section: Introductionmentioning

confidence: 99%

Functional Genomic Screening During Somatic Cell Reprogramming Identifies DKK3 as a Roadblock of Organ Regeneration

et al. 2021

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Somatic cell reprogramming and tissue repair share relevant factors and molecular programs. Here, Dickkopf-3 (DKK3) is identified as novel factor for organ regeneration using combined transcription-factor-induced reprogramming and RNA-interference techniques. Loss of Dkk3 enhances the generation of induced pluripotent stem cells but does not affect de novo derivation of embryonic stem cells, three-germ-layer differentiation or colony formation capacity of liver and pancreatic organoids. However, DKK3 expression levels in wildtype animals and serum levels in human patients are elevated upon injury. Accordingly, Dkk3-null mice display less liver damage upon acute and chronic failure mediated by increased proliferation in hepatocytes and LGR5 + liver progenitor cell population, respectively. Similarly, recovery from experimental pancreatitis is accelerated. Regeneration onset occurs in the acinar compartment accompanied by virtually abolished canonical-Wnt-signaling in Dkk3-null animals. This results in reduced expression of the Hedgehog repressor Gli3 and increased Hedgehog-signaling activity upon Dkk3 loss. Collectively, these data reveal Dkk3 as a key regulator of organ regeneration via a direct, previously unacknowledged link between DKK3, canonical-Wnt-, and Hedgehog-signaling.

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Wnt/β‐catenin signalling controls bile duct regeneration by regulating differentiation of ductular reaction cells

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 8 publications

References 53 publications

Activated hepatic stellate cells promote expansion of LGR5-positive progenitor cells in fibrotic human liver disease

Activated hepatic stellate cells promote expansion of LGR5-positive progenitor cells in fibrotic human liver disease

Automated image analysis of keratin 7 staining can predict disease outcome in primary sclerosing cholangitis

Functional Genomic Screening During Somatic Cell Reprogramming Identifies DKK3 as a Roadblock of Organ Regeneration

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