Wnt/β-Catenin Signaling Induces the Aging of Mesenchymal Stem Cells through the DNA Damage Response and the p53/p21 Pathway

Zhang, Dayong; Wang, Haijie; Tan, Yaohong

doi:10.1371/journal.pone.0021397

Cited by 175 publications

(145 citation statements)

References 42 publications

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“…Our study builds on previous work implicating β-catenin in the regulation of genome stability (Aoki et al, 2007;Dose et al, 2014) and in the DNA damage response (Chandra et al, 2015;Priolli et al, 2013;Tavana et al, 2013;Xu et al, 2008;Zhang et al, 2011). Indeed, our data align well with these previous reports.…”

Section: Discussionsupporting

confidence: 90%

Nuclear α-catenin mediates the DNA damage response via β-catenin and nuclear actin

Serebryannyy

Yemelyanov

Gottardi

et al. 2017

Journal of Cell Science

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α-Catenin is an F-actin-binding protein widely recognized for its role in cell-cell adhesion. However, a growing body of literature indicates that α-catenin is also a nuclear protein. In this study, we show that α-catenin is able to modulate the sensitivity of cells to DNA damage and toxicity. Furthermore, nuclear α-catenin is actively recruited to sites of DNA damage. This recruitment occurs in a β-catenindependent manner and requires nuclear actin polymerization. These findings provide mechanistic insight into the WNT-mediated regulation of the DNA damage response and suggest a novel role for the α-catenin-β-catenin complex in the nucleus.

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Section: Discussionsupporting

confidence: 90%

Nuclear α-catenin mediates the DNA damage response via β-catenin and nuclear actin

Serebryannyy

Yemelyanov

Gottardi

et al. 2017

Journal of Cell Science

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“…Recently, it has also been shown that Wnt1 might induce senescence in mesenchymal cells. 24 Interestingly, atorvastatin at 10 À 5 M induced the expression of Wnt1 and its downstream effector WISP-2 ( Figure 6), a repressor of the TGF-b pathway. 26 We also investigated senescence in vivo using p21 and b-galactosidase staining in rats treated for 1 week with atorvastatin 3 and 5 weeks after BDL (Figures 7 and 8).…”

Section: Discussionmentioning

confidence: 96%

“…24 We investigated this as a third line of evidence for increased senescence of MFB upon incubation with atorvastatin. Indeed at a concentration of 10 À 4 M, Wnt1 expression was undetectable, but mRNA levels of Wnt1 were highly increased at concentrations of 10 À 5 and 10 À 6 M (Figure 6d).…”

Section: Atorvastatin Incubation Induced Senescence In Mfbmentioning

confidence: 99%

“…[19][20][21] Further markers of senescence are increased expression of p21, 22,23 as well as activation of the Wnt pathway. 24 WNT1-inducible-signaling pathway protein 2 (WISP-2) (CCN5), a component of the Wnt pathway, mediates growth arrest and blunts TGF-b-induced effects. 25,26 The present study addresses the cellular effects of atorvastatin on hepatic MFB in vitro and in vivo with special emphasis on proliferation, apoptosis and senescence.…”

mentioning

confidence: 99%

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Atorvastatin inhibits proliferation and apoptosis, but induces senescence in hepatic myofibroblasts and thereby attenuates hepatic fibrosis in rats

Klein

Klösel

Schierwagen

et al. 2012

Laboratory Investigation

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Hepatic myofibroblasts (MFB) show increased proliferation, migration and collagen production, which are crucial for hepatic fibrogenesis. Atorvastatin treatment inhibits proliferation, apoptosis and cytokine production of MFB in bile ductligated (BDL) rats in vivo. Here, we have further investigated the underlying mechanisms. Primary rat hepatic stellate cells (HSC) were isolated and culture-activated to hepatic MFB. Following 3 days of incubation with atorvastatin (10 À 4 , 10 À 5 and 10 À 6 M), transcription levels of profibrotic cytokines (transforming growth factor-b1, connective tissue growth factor and TIMP1) and procollagen Ia were analyzed by real time PCR. Proliferation was investigated by 5'-bromo-2'-deoxyuridine assays. a-Smooth muscle actin protein expression was examined by western blotting. Fluorescence-activated cell sorting analysis of Annexin V and propidium iodide were used to measure apoptosis. Furthermore, p21 western blotting and b-galactosidase staining were investigated in MFB as senescence markers. Subsequently, hepatic expression of desmin and senescence markers were analyzed in the livers of rats receiving atorvastatin (15 mg/kg*d) for 1 week starting 3 and 5 weeks after BDL. Atorvastatin inhibited the activation of HSC to MFB and decreased cytokine and collagen production in MFB in vitro. In addition, proliferation, cytokine and collagen production of MFB were reduced by atorvastatin. Atorvastatin initiated apoptosis at 10 À 4 M and attenuated it at 10 À 5 M. Atorvastatin induced p21 protein expression and b-galactosidase staining of MFB in vitro and in vivo. Atorvastatin elicits similiar effects on MFB as previously seen in vivo: it decreases MFB turnover and fibrogenesis. We suggest that a further mechanism explaining these effects is senescence of cells.

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“…After sterilization under UV light in a 24‐well plate, the patches were washed with PBS and then immersed in DMEM for 2 hrs before use. MSCs were isolated from bone marrow of male SD rats 18. All animals were obtained from the Medical Institute Animal Center of Fudan University.…”

Section: Methodsmentioning

confidence: 99%

Mesenchymal stem cell‐loaded cardiac patch promotes epicardial activation and repair of the infarcted myocardium

Wang

et al. 2017

J Cellular Molecular Medi

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Cardiac patch is considered a promising strategy for enhancing stem cell therapy of myocardial infarction (MI). However, the underlying mechanisms for cardiac patch repairing infarcted myocardium remain unclear. In this study, we investigated the mechanisms of PCL/gelatin patch loaded with MSCs on activating endogenous cardiac repair. PCL/gelatin patch was fabricated by electrospun. The patch enhanced the survival of the seeded MSCs and their HIF‐1α, Tβ4, VEGF and SDF‐1 expression and decreased CXCL14 expression in hypoxic and serum‐deprived conditions. In murine MI models, the survival and distribution of the engrafted MSCs and the activation of the epicardium were examined, respectively. At 4 weeks after transplantation of the cell patch, the cardiac functions were significantly improved. The engrafted MSCs migrated across the epicardium and into the myocardium. Tendency of HIF‐1α, Tβ4, VEGF, SDF‐1 and CXCL14 expression in the infarcted myocardium was similar with expression in vitro. The epicardium was activated and epicardial‐derived cells (EPDCs) migrated into deep tissue. The EPDCs differentiated into endothelial cells and smooth muscle cells, and some of EPDCs showed to have differentiated into cardiomyocytes. Density of blood and lymphatic capillaries increased significantly. More c‐kit+ cells were recruited into the infarcted myocardium after transplantation of the cell patch. The results suggest that epicardial transplantation of the cell patch promotes repair of the infarcted myocardium and improves cardiac functions by enhancing the survival of the transplanted cells, accelerating locality paracrine, and then activating the epicardium and recruiting endogenous c‐kit+ cells. Epicardial transplantation of the cell patch may be applied as a novel effective MI therapy.

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Wnt/β-Catenin Signaling Induces the Aging of Mesenchymal Stem Cells through the DNA Damage Response and the p53/p21 Pathway

Cited by 175 publications

References 42 publications

Nuclear α-catenin mediates the DNA damage response via β-catenin and nuclear actin

Nuclear α-catenin mediates the DNA damage response via β-catenin and nuclear actin

Atorvastatin inhibits proliferation and apoptosis, but induces senescence in hepatic myofibroblasts and thereby attenuates hepatic fibrosis in rats

Mesenchymal stem cell‐loaded cardiac patch promotes epicardial activation and repair of the infarcted myocardium

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