Activated Wnt signaling induces myofibroblast differentiation of mesenchymal stem cells, contributing to pulmonary fibrosis

Sun, Zhaorui; Wang, Cong; Shi, Chaowen; Sun, Fangfang; Xu, Xiaomeng; Qian, Weiping; Nie, Shaoping; Han, Xiaodong

doi:10.3892/ijmm.2014.1672

Cited by 54 publications

(51 citation statements)

References 46 publications

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“…STAT3 and AKT are hyperphosphorylated, Wnt/b-catenin pathway activated, and a-SMA overexpressed in lung fibroblasts isolated from the lungs of patients with idiopathic fibrosis (55)(56)(57). These overexpressions are associated with an overproduction of extracellular matrix and the promotion of fibroblast chemotaxis, proliferation, and differentiation (57,58). Activation of STAT3, AKT, and Wnt/ b-catenin pathways was also reported in mouse models of lung fibrosis (59,60).…”

Section: Discussionmentioning

confidence: 87%

“…In addition, increasing evidence suggests a role of these pathways in lung fibrosis. STAT3 and AKT are hyperphosphorylated, Wnt/b-catenin pathway activated, and a-SMA overexpressed in lung fibroblasts isolated from the lungs of patients with idiopathic fibrosis (55)(56)(57). These overexpressions are associated with an overproduction of extracellular matrix and the promotion of fibroblast chemotaxis, proliferation, and differentiation (57,58).…”

Section: Discussionmentioning

confidence: 99%

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Niclosamide Prevents Systemic Sclerosis in a Reactive Oxygen Species–Induced Mouse Model

Morin

Kavian

Nicco

et al. 2016

The Journal of Immunology

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Systemic sclerosis (SSc) is a connective tissue disorder characterized by fibrosis of the skin and inner organs, vasculopathy, and immunological abnormalities. Recent insights on the implication of STAT3, AKT, and Wnt/β-catenin in fibrosis have prompted us to investigate, in a mouse model of ROS-induced SSc, the effects of niclosamide, an antihelmintic drug that inhibits both of these signaling pathways. SSc was induced in BALB/c mice by daily s.c. injections of hypochlorous acid (HOCl). Mice were treated or not every other day, 5 d a week, for 6 wk, by niclosamide. Skin and lung fibrosis as well as immunological features were studied. Mice exposed to HOCl developed a diffuse cutaneous SSc with pulmonary fibrosis and anti-DNA topoisomerase 1 autoantibodies. STAT3, AKT, and Wnt/β-catenin pathways were hyperactivated in the skin and the lungs of diseased mice. Niclosamide reversed fibrosis of the skin and the lungs. Beneficial immunological effects were also observed because niclosamide decreased the activation of CD4+ and CD8+ T cells, autoimmune B cell activation, as well as IL-4 and IL-13 production in the skin. The improvement permitted by niclosamide in the mouse model of HOCl-induced SSc as well as the well-documented safety profile of this drug provide a rationale for the evaluation of niclosamide in the management of patients affected by this disease.

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Section: Discussionmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Niclosamide Prevents Systemic Sclerosis in a Reactive Oxygen Species–Induced Mouse Model

Morin

Kavian

Nicco

et al. 2016

The Journal of Immunology

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“…Recently, b-catenin/Wnt signaling has been found to be crucial for myofibroblast formation in fibrotic diseases, such as pulmonary fibrosis and hypertrophic scar formation. 29,31 The importance of sustained b-catenin/Wnt signaling in fibrotic diseases is rapidly being realized, and developments to target this pathway in organ fibrosis are ongoing. 42 Although b-catenin/Wnt signaling is not currently being targeted to treat TED, our new findings and a recent report revealing increased Wnt pathway gene expression in TED tissue compared with control tissue suggests further investigation could be beneficial.…”

Section: Discussionmentioning

confidence: 99%

“…In b-catenin/Wnt signaling, Wnt family member proteins trigger phosphorylation of GSK3b, which in turn stabilize b-catenin proteins and allow b-catenin to translocate into the nucleus and activate transcription of Wnt-responsive genes, some of which are essential for myofibroblast formation. 29,31 Interestingly, TGF-b itself, without the need for Wnt, triggers phosphorylation of GSK3b to induce b-catenin nuclear translocation and activation. 32 To measure b-catenin/Wnt signaling, we analyzed phospho-GSK3b levels in orbital fibroblasts treated with or without TGF-b and the AHR ligands ITE and FICZ ( Figure 8A and Supplemental Figure S5).…”

Section: Ahr Activation By Ite and Ficz Blocks B-catenin/wnt Signalinmentioning

confidence: 99%

The Aryl Hydrocarbon Receptor and Its Ligands Inhibit Myofibroblast Formation and Activation

Woeller

Roztocil

Hammond

et al. 2016

The American Journal of Pathology

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Thyroid eye disease (TED) is a degenerative disease that manifests with detrimental tissue remodeling, myofibroblast accumulation, and scarring in the orbit of affected individuals. Currently, there are no effective therapies for TED that target or prevent the excessive tissue remodeling caused by myofibroblast formation and activation. The canonical cytokine that induces myofibroblast formation is transforming growth factor (TGF)-b. The TGF-b signaling pathway is influenced by aryl hydrocarbon receptor (AHR) signaling pathways. We hypothesized that AHR agonists can prevent myofibroblast formation in fibroblasts from patients with TED, and thus AHR ligands are potential therapeutics for the disease. Orbital fibroblasts explanted from patients with TED were treated with TGF-b to induce myofibroblast formation, contraction, and proliferation. We found that AHR ligands prevent TGF-b edependent myofibroblast formation, and this ability is dependent on AHR expression. The AHR and AHR ligands block profibrotic Wnt signaling by inhibiting the phosphorylation of GSK3b to prevent myofibroblast formation. These results provide new insight into the molecular pathways underlying orbital scarring in TED. These novel studies highlight the potential of the AHR and AHR ligands as future therapeutic options for eye diseases and possibly also for other scarring conditions. (Am J Pathol 2016, 186: 3189e3202; http://dx

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“…Total protein concentrations were measured using Bicinchoninic acid (BCA) reagent (Beyotime Biotech, Jiangsu, China) were used to determine the protein concentration. Western blot was performed as previously described (29). Briefly, Proteins were separated in 10% sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and were then electrophoretically transferred onto polyvinylidene fluoride (PVDF) membranes at 200 mA for 60-120 min.…”

Section: Ea S U Re M En T Of Hyd Rox Yproli N E Co N Cen T Ra T Io Nmentioning

confidence: 99%

Inhibition of penile tunica albuginea myofibroblasts activity by adipose‑derived stem cells

et al. 2017

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Abstract. The activation of tunica albuginea myofibroblasts (MFs) serves an essential role in Peyronie's disease (PD). Increasing evidence has reported that adipose tissue-derived stem cells (ADSCs) have been demonstrated to attenuate the symptoms of PD in animal models. However, the mechanisms of the antifibrotic effects of ADSCs in PD remain to be fully elucidated. In the present study, the inhibitory effects and possible mechanism of ADSCs on the activation of MFs derived from rat penile tunica albuginea were investigated. ADSCs were obtained from the paratesticular fat of Sprague Dawley rats. MFs were transformed from rat penile tunica albuginea fibroblasts through stimulation with 5 ng/ml tumor growth factor-β1. Transwell cell cultures were adopted for co-culture of ADSCs and MFs. Western blot analysis was used to assess changes in the expression levels of α smooth muscle actin (αSMA), collagen I, phosphorylated (p)-SMAD family member 2 (Smad2), Smad2, ras homolog family member A (RhoA), Rho associated coiled-coil containing protein kinase (ROCK)1 and ROCK2, caspase3, caspase9, and matrix metalloproteinases (MMPs). Collagen gel assays were used to assess cell contractility. Additionally, the concentration of hydroxyproline in the culture medium was detected using commercially available kits. It was demonstrated that ADSCs reduced the expression of αSMA and collagen I of MFs. Furthermore, p-Smad2, RhoA, ROCK1 and ROCK2 expression was significantly reduced in the MFs+ADSCs group compared with that in the MFs-only culture, while the expression of MMPs (MMP2, MMP3, MMP9 and MMP13) and caspases (caspase3 and caspase9) was upregulated. In addition, ADSCs were able to downregulate the concentration of hydroxyproline in the culture medium of MFs and reverse the contraction of MFs. Collectively, these results suggested that ADSCs inhibited the activation of MFs, decreased collagen production, and suppressed the contraction of myofibroblasts, via Smad and RhoA/ROCK signaling pathways. Furthermore, ADSCs reduced the deposition of collagen and promoted the apoptosis of MFs via MMPs, and caspases. Accordingly, the application of ADSCs may provide a novel therapeutic strategy for PD.

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Activated Wnt signaling induces myofibroblast differentiation of mesenchymal stem cells, contributing to pulmonary fibrosis

Cited by 54 publications

References 46 publications

Niclosamide Prevents Systemic Sclerosis in a Reactive Oxygen Species–Induced Mouse Model

Niclosamide Prevents Systemic Sclerosis in a Reactive Oxygen Species–Induced Mouse Model

The Aryl Hydrocarbon Receptor and Its Ligands Inhibit Myofibroblast Formation and Activation

Inhibition of penile tunica albuginea myofibroblasts activity by adipose‑derived stem cells

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