Inhibition of Wnt/β-catenin signaling promotes epithelial differentiation of mesenchymal stem cells and repairs bleomycin-induced lung injury

Wang, Cong; Zhu, Huiming; Sun, Zhaorui; Zou, Xiang; Ge, Yuanyuan; Ni, Can; Luo, Zhaowen; Qian, Weiping; Han, Xiaodong

doi:10.1152/ajpcell.00366.2013

Cited by 91 publications

(70 citation statements)

References 41 publications

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“…XAV939 has previously been demonstrated to effectively suppress bleomycin-induced PF in vivo by inhibiting Wnt/β-catenin signaling (Wang et al, 2014). We reproduced this model in the current study and demonstrated again that XAV939 significantly reduced the severity of PF as assessed by H&E (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Mice were sacrificed 7 or 14 days after bleomycin instillation. Mouse lungs were obtained for histopathologic analysis and collagen assay (Wang et al, 2014). …”

Section: Methodsmentioning

confidence: 99%

“…For the evaluation of the effect of XAV 939, a small-molecule compound that specifically inhibits Wnt/β-catenin signaling (Wang et al, 2014), 10 days after administration of bleomycin, XAV939 was administered intraperitoneally at 5 mg/kg for 11 consecutive days. Mice were sacrificed 21 days after bleomycin instillation.…”

Section: Methodsmentioning

confidence: 99%

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Inhibition of Wnt/β-catenin signaling suppresses bleomycin-induced pulmonary fibrosis by attenuating the expression of TGF-β1 and FGF-2

Chen

Shi

Meng

et al. 2016

Experimental and Molecular Pathology

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Pulmonary fibrosis is a progressive lung disorder of unknown etiology, which is characterized by alterations in alveolar epithelium function, fibroblast activation, and increased extracellular matrix deposition. Recent studies have demonstrated that PF is associated with uncontrolled production of cytokines after lung injury. In the present study, we found that transforming growth factor-β1 (TGF-β1) and fibroblast growth factor 2 (FGF-2) were both upregulated in bleomycin-induced fibrotic lung tissue and primary murine alveolar epithelial Type II (ATII) cells treated with bleomycin. Furthermore, we discovered that TGF-β1 could induce the differentiation of lung resident mesenchymal stem cells (LR-MSCs) into fibroblasts, which may play an essential role in PF. LR-MSCs incubated with FGF-2 showed modest alterations in the expression of α-SMA and Vimentin. Moreover, in our study, we found that Wnt/β-catenin signaling was activated both in vitro and in vivo as a result of bleomycin treatment. Interestingly, we also found that suppression of the Wnt/β-catenin signaling could significantly attenuate bleomycin-induced PF accompanied with decreased expression of TGF-β1 and FGF-2 in vitro and in vivo. These results support that controlling the aberrant expression of TGF-β1 and FGF-2 via inhibition of Wnt/β-catenin signaling could serve as a potential therapeutic strategy for PF.

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Section: Resultsmentioning

confidence: 99%

“…Mice were sacrificed 7 or 14 days after bleomycin instillation. Mouse lungs were obtained for histopathologic analysis and collagen assay (Wang et al, 2014). …”

Section: Methodsmentioning

confidence: 99%

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Inhibition of Wnt/β-catenin signaling suppresses bleomycin-induced pulmonary fibrosis by attenuating the expression of TGF-β1 and FGF-2

Chen

Shi

Meng

et al. 2016

Experimental and Molecular Pathology

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“…Immunofluorescence analysis was performed as described previously (Wang et al, 2014). The following primary antibodies were employed: Rabbit anti-zonula occludens-1 (ZO-1); rabbit anti-occludin (all antibodies were purchased from Abcam, Cambridge, MA).…”

Section: Methodsmentioning

confidence: 99%

The toxic effects of microcystin-LR on mouse lungs and alveolar type II epithelial cells

Wang

Yin

et al. 2016

Toxicon

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Objectives Microcystin-leucine arginine (MC-LR) is produced by cyanobacteria and can accumulate in lungs through blood circulation. However, the effect of MC-LR on lung remains unclear. In this study, we investigated the chronic, low-dose effect of MC-LR on mouse lung tissues and the influence of MC-LR on mouse alveolar type II epithelial cells (ATII cells). Methods MC-LR was orally administered to mice at 0, 1, 10, and 40 μg/L for 6 consecutive months and mouse lungs were obtained for histopathological and immunoblot analysis. ATII cells were cultured in various concentrations of MC-LR (0, 0.5, 5, 50, 500 nmol/L) for indicated time and the cell viability and proteins change were tested. Results Our study revealed that the chronic, low-dose MC-LR exposure induced alveolar collapse and lung cell apoptosis as well as the breach of cell junction integrity. Furthermore, following treatment with MC-LR, ATII cells could uptake MC-LR, resulting in apoptosis and disruption of cell junction integrity. Conclusions These data support the toxic potential of low-dose MC-LR in rendering chronic injury to lung tissues.

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“…Researches showed that the Wnt/β-catenin pathway is hyperactivated in lung from a subset of patients with IPF [17,18], and Wnt-3α promoted myofibroblast differentiation via Smad-dependent TGF-β signaling [19]. Our group have found that activated Wnt signaling induces myofibroblast differentiation of mesenchymal stem cells and inhibition of Wnt/β-catenin signaling promotes engraftment and epithelial differentiation of mesenchymal stem cells to repair lung injury [20][21][22]. Upon activation, β-catenin and Lef1/Tcf, which are downstream components of the Wnt signaling cascade, form a complex with Smad4, an essential mediator of signals initiated by TGF-β, then translocate to the nucleus to participate in transcription [23].…”

Section: Introductionmentioning

confidence: 94%

Targeted inhibition of disheveled PDZ domain via NSC668036 depresses fibrotic process

Wang

Dai

Sun

et al. 2015

Experimental Cell Research

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Inhibition of Wnt/β-catenin signaling promotes epithelial differentiation of mesenchymal stem cells and repairs bleomycin-induced lung injury

Abstract: . Inhibition of Wnt/␤-catenin signaling promotes epithelial differentiation of mesenchymal stem cells and repairs bleomycininduced lung injury.

Cited by 91 publications

References 41 publications

Inhibition of Wnt/β-catenin signaling suppresses bleomycin-induced pulmonary fibrosis by attenuating the expression of TGF-β1 and FGF-2

Inhibition of Wnt/β-catenin signaling suppresses bleomycin-induced pulmonary fibrosis by attenuating the expression of TGF-β1 and FGF-2

The toxic effects of microcystin-LR on mouse lungs and alveolar type II epithelial cells

Targeted inhibition of disheveled PDZ domain via NSC668036 depresses fibrotic process

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