YAP Activates Pancreatic Stellate Cells and Enhances Pancreatic Fibrosis

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.