Abstract
IntroductionHepatic ischemia/reperfusion (I/R) injury is a major complication after liver resection, liver transplantation, and trauma, however, the precise mechanisms of liver recovery after I/R have not been elucidated. The Hippo signaling pathway and their downstream effectors, Yes‐associated protein (YAP) and transcriptional co‐activator with PDZ‐binding motif (TAZ), have been identified as key regulators of regulating cell proliferation and organ size. In the current study, we sought to determine the expression of YAP and TAZ and their contribution to liver recovery after I/R.MethodsA murine model of partial hepatic ischemia/reperfusion (I/R) was used to study liver recovery after injury. Hepatic stellate cell and portal fibroblast in liver tissue were assessed by immunonhistochemical staining for desmin. Tissue levels of PDGF‐BB and TGF‐b1 were measured by enzyme‐linked immunosorbent assay (ELISA). The expression of YAP/TAZ and their related protein were measured by immunohistochemical staining and Western blot. Proliferation of desmin positive cell was assessed by dual immunofluorescence staining for desmin and proliferationg cell nuclear antigen (PCNA).ResultsStellate cells and portal fibroblasts, which stained positive for desmin, proliferated around portal veins during early recovery periods. Proliferation of these cells correlated with increased liver expression of PGDF‐BB and TGF‐b1. The expression of phosphorylated LATS1 and phosphorylated MOB1 which sequester YAP/TAZ in the cytoplasm were decreased in liver tissue and nuclear staining of both YAP and TAZ was evident in desmin‐positive cells during liver recovery after I/R. Pharmacological inhibition of YAP and TAZ using verteporfin attenuated desmin positive cell proliferation after I/R.ConclusionThe data suggest that hepatic stellate cell and/or portal fibroblasts expand during liver recovery after I/R and YAP/TAZ regulate their proliferation.
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