Abstract
The role of persistent activation of pancreatic stellate cells (PSCs) in the fibrosis associated with chronic pancreatitis (CP) is increasingly being recognized. Recent studies have shown that Wnt signaling is involved in the development of fibrosis in multiple organs, however, the role of specific Wnts in pancreatic fibrosis remains unknown. We investigated the role of Wnt signaling during PSC activation in CP and the effect of β-catenin inhibition and Dickkopf-related protein 1 (Dkk1) restoration on the phenotype of PSCs. CP was induced in mice by repetitive caerulein injection and mouse PSCs were isolated and activated in vitro. The expression of Wnts, β-catenin, secreted frizzled-related proteins (sFRPs) and Dkks was analyzed by quantitative RT-PCR and western blotting. The canonical Wnt signaling pathway was examined by immunofluorescence and western blot detection of nuclear β-catenin expression. The effect of recombinant mouse Dkk-1 (rmDkk-1) on cell proliferation and apoptosis was assessed by flow cytometry, immunofluorescence, immunocytochemistry and Cell Counting Kit-8 (CCK-8) analysis. The expression of β-catenin, collagen1α1, TGFβRII, PDGFRβ and α-SMA in PSCs treated with different concentrations of rmDkk-1 or siRNA against β-catenin was determined by quantitative RT-PCR and western blotting. Wnt2 was the only Wnt whose expression was significantly upregulated in response to PSC activation, and Wnt2 and β-catenin protein levels were significantly increased in the pancreas of CP mice, whereas Dkk-1 expression was evidently decreased. Nuclear β-catenin levels were markedly increased in activated PSCs, and rmDkk-1 suppressed the nuclear translocation of β-catenin and the proliferation and extracellular matrix production of PSCs through the downregulation of PDGFRβ and TGFβRII. Upregulation of Dkk-1 expression increased apoptosis in cultured PSCs. These results indicate that Wnt signaling may mediate the profibrotic effect of PSC activation, and Wnt2/Dkk-1 could be potential therapeutic targets for CP.
Highlights
Chronic pancreatitis (CP) is characterized by progressive pancreatic fibrosis
We investigated whether the effect of recombinant mouse Dickkopf protein families (Dkks)-1 (rmDkk-1) was mediated by the induction of apoptosis in pancreatic stellate cells (PSCs) by annexin-V/propidium iodide (PI) staining and found that exposure to rmDkk-1 increased the rate of apoptosis, especially at a dose of 200 ng/ml (Figure 7A)
Little is known about the role of Wnt signaling in pancreatic fibrosis, a process in which PSCs play an important role
Summary
The persistent activation of pancreatic stellate cells (PSCs) plays a pivotal role in pancreatic fibrogenesis, while the redifferentiation and outcome of activated PSCs determines the pathological outcome after pancreatic injury [1,2,3]. The transient activation of PSCs during acute pancreatitis suggests that a negative feedback mechanism regulates PSC activation [4]. Studies have shown that restoration of quiescence in activated PSCs may provide a novel therapeutic strategy for CP [5,6]. Several inflammatory mediators released during the development of pancreatitis have the potential to regulate PSCs, accumulating evidence supports major roles for platelet-derived growth factor (PDGF), transforming growth factor (TGF)-b1 and angiotensin II as key modulators of the persistently activated and profibrotic phenotype of these cells [7]. The mechanism of PSC activation has been examined in recent studies [4], the precise molecular mechanisms underlying the persistent activation process remain to be elucidated
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