The WNT signaling pathways in wound healing and fibrosis

Burgy, Olivier; Königshoff, Mélanie

doi:10.1016/j.matbio.2018.03.017

Cited by 149 publications

(118 citation statements)

References 111 publications

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“…While the important role of Wnt/β-catenin signaling in the development of fibrosis has been well documented, the mechanism of how this pathway drives fibrosis is not completely clear. Increased proliferation and activation of mesenchymal cells such fibroblasts and hepatic stellate cells by the activation of Wnt/β-catenin signaling pathway were reported to contribute to the development of fibrosis [26]. In our in vitro study, we found little or no evidence that RSPO3 treatment affects any of potential pro-fibrotic activity in these cells.…”

Section: Discussioncontrasting

confidence: 64%

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Targeting the Wnt signaling pathway through R-spondin 3 identifies an anti-fibrosis treatment strategy for multiple organs

Zhang¹,

Haughey²,

Wang³

et al. 2020

PLoS ONE

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The Wnt/β-catenin signaling pathway has been implicated in human proliferative diseases such as cancer and fibrosis. The functions of β-catenin and several other components of this pathway have been investigated in fibrosis. However, the potential role of R-spondin proteins (RSPOs), enhancers of the Wnt/β-catenin signaling, has not been described. A specific interventional strategy targeting this pathway for fibrosis remains to be defined. We developed monoclonal antibodies against members of the RSPO family (RSPO1, 2, and 3) and probed their potential function in fibrosis in vivo. We demonstrated that RSPO3 plays a critical role in the development of fibrosis in multiple organs. Specifically, an anti-RSPO3 antibody, OMP-131R10, when dosed therapeutically, attenuated fibrosis in carbon tetrachloride (CCl 4 )-induced liver fibrosis, bleomycin-induced pulmonary and skin fibrosis models. Mechanistically, we showed that RSPO3 induces multiple pro-fibrotic chemokines and cytokines in Kupffer cells and hepatocytes. We found that the anti-fibrotic activity of OMP-131R10 is associated with its inhibition of β-catenin activation in vivo. Finally, RSPO3 was found to be highly elevated in the active lesions of fibrotic tissues in mouse models of fibrosis and in patients with idiopathic pulmonary fibrosis (IPF) and nonalcoholic steatohepatitis (NASH). Together these data provide an anti-fibrotic strategy for targeting the Wnt/β-catenin pathway through RSPO3 blockade and support that OMP-131R10 could be an important therapeutic agent for fibrosis. PLOS ONEPLOS ONE | https://doi.org/10.

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Section: Discussioncontrasting

confidence: 64%

“…The mechanisms of Wnt/β-catenin driven fibrosis seem to be complex and are not fully understood [26]. We showed the RSPO3 pro-fibrotic activity is strongly associated with the activation of Wnt/β-catenin signaling.…”

Section: Rspo3 Induces Multiple Fibrotic Mediatorsmentioning

confidence: 86%

Targeting the Wnt signaling pathway through R-spondin 3 identifies an anti-fibrosis treatment strategy for multiple organs

Zhang¹,

Haughey²,

Wang³

et al. 2020

PLoS ONE

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“…The altered membrane localization of β-catenin in PMT-treated luminal epithelial cells shows engagement with cadherins and altered apico-basal cell polarity, which is associated with tumour progression [54]. Finally, the increase in expression of active β-catenin in PMT-treated spleens is restricted to the parenchyma that is comprised of connective tissue cells which are known targets of PMT [18], and Wnt/β-catenin signaling is classically associated with fibrosis [55]. Thus, given that β-catenin has multiple cellular functions involving Wnt signalling activation, maintaining adhesion junctions, and acting as a transcription factor [56], it would be interesting in the future to further dissect the cell types in which β-catenin is activated and explore the functional role of the PMT-activated β-catenin in these tissues.…”

Section: Discussionmentioning

confidence: 99%

In Vivo Targets of Pasteurella Multocida Toxin

Banu

Lax

Grigoriadis

2020

IJMS

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Many Pasteurella multocida strains are carried as commensals, while some cause disease in animals and humans. Some type D strains cause atrophic rhinitis in pigs, where the causative agent is known to be the Pasteurella multocida toxin (PMT). PMT activates three families of G-proteins-G q/11 , G 12/13 , and G i/o -leading to cellular mitogenesis and other sequelae. The effects of PMT on whole animals in vivo have been investigated previously, but only at the level of organ-specific pathogenesis. We report here the first study to screen all the organs targeted by the toxin by using the QE antibody that recognizes only PMT-modified G-proteins. Under our experimental conditions, short-term treatment of PMT is shown to have multiple in vivo targets, demonstrating G-alpha protein modification, stimulation of proliferation markers and expression of active β-catenin in a tissue-and cell-specific manner. This highlights the usefulness of PMT as an important tool for dissecting the specific roles of different G-alpha proteins in vivo.

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“…It was thought that the remaining seven keloids did not coexpress these markers because their endothelial cells had already gone through EndoMT. In the same study, Lee et al showed that Wnt-3a, (whose signals play a critical role in fibrosis [49]), may drive EndoMT in keloids. Thus, they first showed that keloid tissues expressed high levels of Wnt-3a.…”

Section: Endomt-derived Myofibroblasts In Skin Fibrosismentioning

confidence: 92%

The Vascular Involvement in Soft Tissue Fibrosis—Lessons Learned from Pathological Scarring

Huang

Ogawa

2020

IJMS

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Soft tissue fibrosis in important organs such as the heart, liver, lung, and kidney is a serious pathological process that is characterized by excessive connective tissue deposition. It is the result of chronic but progressive accumulation of fibroblasts and their production of extracellular matrix components such as collagens. Research on pathological scars, namely, hypertrophic scars and keloids, may provide important clues about the mechanisms that drive soft tissue fibrosis, in particular the vascular involvement. This is because these dermal fibrotic lesions bear all of the fibrotic characteristics seen in soft tissue fibrosis. Moreover, their location on the skin surface means they are readily observable and directly treatable and therefore more accessible to research. We will focus here on the roles that blood vessel-associated cells play in cutaneous scar pathology and assess from the literature whether these cells also contribute to other soft tissue fibroses. These cells include endothelial cells, which not only exhibit aberrant functions but also differentiate into mesenchymal cells in pathological scars. They also include pericytes, hepatic stellate cells, fibrocytes, and myofibroblasts. This article will review with broad strokes the roles that these cells play in the pathophysiology of different soft tissue fibroses. We hope that this brief but wide-ranging overview of the vascular involvement in fibrosis pathophysiology will aid research into the mechanisms underlying fibrosis and that this will eventually lead to the development of interventions that can prevent, reduce, or even reverse fibrosis formation and/or progression.

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The WNT signaling pathways in wound healing and fibrosis

Cited by 149 publications

References 111 publications

Targeting the Wnt signaling pathway through R-spondin 3 identifies an anti-fibrosis treatment strategy for multiple organs

Targeting the Wnt signaling pathway through R-spondin 3 identifies an anti-fibrosis treatment strategy for multiple organs

In Vivo Targets of Pasteurella Multocida Toxin

The Vascular Involvement in Soft Tissue Fibrosis—Lessons Learned from Pathological Scarring

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