Non-canonical Wnt signalling regulates scarring in biliary disease via the planar cell polarity receptors

Wilson, David H.; Jarman, Edward J.; Mellin, Ronan; Wilson, Malcolm; Waddell, Scott H.; Tsokkou, Panagiota; Younger, Nicholas T.; Raven, Alexander; Bhalla, S. R.; Noll, A. T. R.; Damink, Steven W. M. Olde; Schaap, Frank G.; Chen, P.; Bates, David O.; Bañales, Jesús M.; Dean, Charlotte; Henderson, Deborah J.; Sansom, Owen J.; Kendall, Timothy J.; Boulter, Luke

doi:10.1038/s41467-020-14283-3

Cited by 39 publications

(43 citation statements)

References 70 publications

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“…WNT pathway signaling is also enriched particularly in cluster 1 (Supplementary Fig. 20b ); JUN is a known transcription factor partner in non-canonical WNT pathway signaling 33 . Taken together these data support JUN as a primary mediator of fibrosis—which occurs through several downstream pathways—in abdominal adhesions in humans.…”

Section: Resultsmentioning

confidence: 99%

Elucidating the fundamental fibrotic processes driving abdominal adhesion formation

et al. 2020

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Adhesions are fibrotic scars that form between abdominal organs following surgery or infection, and may cause bowel obstruction, chronic pain, or infertility. Our understanding of adhesion biology is limited, which explains the paucity of anti-adhesion treatments. Here we present a systematic analysis of mouse and human adhesion tissues. First, we show that adhesions derive primarily from the visceral peritoneum, consistent with our clinical experience that adhesions form primarily following laparotomy rather than laparoscopy. Second, adhesions are formed by poly-clonal proliferating tissue-resident fibroblasts. Third, using single cell RNA-sequencing, we identify heterogeneity among adhesion fibroblasts, which is more pronounced at early timepoints. Fourth, JUN promotes adhesion formation and results in upregulation of PDGFRA expression. With JUN suppression, adhesion formation is diminished. Our findings support JUN as a therapeutic target to prevent adhesions. An anti- JUN therapy that could be applied intra-operatively to prevent adhesion formation could dramatically improve the lives of surgical patients.

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Section: Resultsmentioning

confidence: 99%

Elucidating the fundamental fibrotic processes driving abdominal adhesion formation

et al. 2020

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“…The expression of Rspo family members was not detected in BD organoids, suggesting that other cell types may be responsible for its presence in pathophysiological contexts in vivo. (Wilson et al, 2020). We attribute these apparent discrepancies to differences in the sensitivities of the 10x genomics scRNAseq and RT-qPCR techniques.…”

Section: Discussionmentioning

confidence: 98%

Canonical Wnt signalling is activated during BEC-to-hepatocyte conversionin vivoand modulates liver epithelial cell plasticity in hepatic organoids

Valle-Encinas

Aleksieva

Martinez

et al. 2020

Preprint

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SummaryWhile it is recognized that the Wnt/ß-catenin pathway orchestrates hepatocyte proliferation in both homeostasis and injury, little is known about the importance of β-catenin in biliary epithelial cell (BEC) plasticity. In this study, the dynamics of activation of the canonical Wnt pathway were investigated during BEC-to-hepatocyte conversion using as a model methionine/choline deficient (MCD)-injured livers where hepatocyte proliferation was compromised by the overexpression of p21. In this model, activation of β-catenin was found an event associated with BEC reprogramming. Using ductal organoids to model BECs transitioning into hepatocytes, we found that activation of the Wnt/ß-catenin pathway in these cells promoted partial escape from a biliary fate and triggered the acquisition of progenitor cell features. Our data furthermore support that BECs are source of Wnt ligands and that Rspo proteins potentially act as the limiting factor controlling the activation of β-catenin activation and BEC reprogramming during severe liver damage.

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“…( 21 ) However, these findings remain controversial given that inhibition of WNT/planar cell polarity signaling does not affect intrahepatic cholangiocyte proliferation upon injury in the mouse and the role of this pathway seems to be related more to profibrotic cytokine production. ( 24 ) Even less is known about these processes in the extrahepatic biliary tree. Thus, future research should examine the mechanisms underpinning our observations in vitro , as well as what role canonical versus noncanonical WNT signaling may play in the extrahepatic biliary tree in vivo .…”

Section: Discussionmentioning

confidence: 99%

Regional Differences in Human Biliary Tissues and Corresponding In Vitro–Derived Organoids

et al. 2021

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Background and Aims Organoids provide a powerful system to study epithelia in vitro. Recently, this approach was applied successfully to the biliary tree, a series of ductular tissues responsible for the drainage of bile and pancreatic secretions. More precisely, organoids have been derived from ductal tissue located outside (extrahepatic bile ducts; EHBDs) or inside the liver (intrahepatic bile ducts; IHBDs). These organoids share many characteristics, including expression of cholangiocyte markers such as keratin (KRT) 19. However, the relationship between these organoids and their tissues of origin, and to each other, is largely unknown. Approach and Results Organoids were derived from human gallbladder, common bile duct, pancreatic duct, and IHBDs using culture conditions promoting WNT signaling. The resulting IHBD and EHBD organoids expressed stem/progenitor markers leucine‐rich repeat–containing G‐protein‐coupled receptor 5/prominin 1 and ductal markers KRT19/KRT7. However, RNA sequencing revealed that organoids conserve only a limited number of regional‐specific markers corresponding to their location of origin. Of particular interest, down‐regulation of biliary markers and up‐regulation of cell‐cycle genes were observed in organoids. IHBD and EHBD organoids diverged in their response to WNT signaling, and only IHBDs were able to express a low level of hepatocyte markers under differentiation conditions. Conclusions Taken together, our results demonstrate that differences exist not only between extrahepatic biliary organoids and their tissue of origin, but also between IHBD and EHBD organoids. This information may help to understand the tissue specificity of cholangiopathies and also to identify targets for therapeutic development.

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Non-canonical Wnt signalling regulates scarring in biliary disease via the planar cell polarity receptors

Cited by 39 publications

References 70 publications

Elucidating the fundamental fibrotic processes driving abdominal adhesion formation

Elucidating the fundamental fibrotic processes driving abdominal adhesion formation

Canonical Wnt signalling is activated during BEC-to-hepatocyte conversionin vivoand modulates liver epithelial cell plasticity in hepatic organoids

Regional Differences in Human Biliary Tissues and Corresponding In Vitro–Derived Organoids

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