Background:Pancreatic stellate cells(PSCs)foster the progression of pancreatic adenocarcinoma and chronic pancreatitis(CP)by producing a dense fibrotic stroma.However,the incomplete knowledge of PSCs biology hampers the exploration of antifibrotic therapies.Here,we explored the role of the Hippo pathway in the context of PSCs activation and experimental CP.Methods:CP model was created in rats with the tail vein injection of dibutyltin dichloride(DBTC).The expression of Yes-associated protein(YAP)in CP tissue was assessed.Primary and immortalized rats PSCs were treated with the YAP-inhibitor verteporfin.Furthermore,YAP siRNA was employed.Subsequently,DNA synthesis,cell survival,levels of α-smooth muscle actin(α-SMA)protein,presence of lipid droplets and PSCs gene expression were evaluated.Upstream regulators of YAP signaling were studied by reporter gene assays.Results:In DBTC-induced CP,pronounced expression of YAP in areas of tubular structures and periduc-tal fibrosis was observed.Verteporfin diminished DNA replication in PSCs in a dose-dependent fash-ion.Knockdown of YAP reduced cell proliferation.Primary cultures of PSCs were characterized by a de-crease of lipid droplets and increased synthesis of α-SMA protein.Both processes were not affected by verteporfin.At the non-cytotoxic concentration of 100 nmol/L,verteporfin significantly reduced mRNA levels of transforming growth factor-β1(Tgf-β1)and Ccn family member 1(Ccn1).YAP signaling was acti-vated by TGF-β1,but repressed by interferon-γ.Conclusions:Activated YAP enhanced PSCs proliferation.The antifibrotic potential of Hippo pathway in-hibitors warrants further investigation.

Lennard Spanehl;Denis Revskij;Karen Bannert;Luise Ehlers;Robert Jaster

Department of Medicine Ⅱ,Division of Gastroenterology,Rostock University Medical Center,Ernst-Hey demann-Str.6,18057 Rostock,Germany

国际肝胆胰疾病杂志(英文版)

[1]Lennard Spanehl;Denis Revskij;Karen Bannert;Luise Ehlers;Robert Jaster-.YAP activates pancreatic stellate cells and enhances pancreatic fibrosis)[J].国际肝胆胰疾病杂志(英文版),2022(06):583-589

antifibrotic,periduc,Ccn,Ccn1

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