Applying the brakes: Does Prostaglandin Dehydrogenase promote mitotic quiescence in differentiated human urothelium?

The urothelium functions to provide and maintain a tight barrier in the urinary tract whilst retaining the ability to shift phenotype from being mitotically quiescent to rapidly regenerative in the event of injury or infection. Previous observations in the human urothelium have identified bioactive eicosanoids are released upon urothelial damage and can be synthesised within the urothelium itself. However limited studies have been performed to understand the roles, if any, of eicosanoid prostaglandin E2 in mediating normal urothelial tissue homeostasis. The aim of this study was to investigate the expression of components of the PGE2 metabolic pathway in human urothelial cells and assess the function in regulating mitotic quiescence and urothelial wound repair. Prostaglandin dehydrogenase (PGDH), whose function is to inactivate PGE2, was identified as having a differentiation-associated expression and localisation in normal human urothelial (NHU) cells in vitro and in situ. Pharmacological inhibition of PGDH activity disrupted mitotic quiescence by releasing urothelial cells into the cell cycle which suggested PGDH may function to retain cells in the G0 quiescent phase. PGDH inhibition also reduced barrier reformation during urothelial wound repair, and this was a cAMP-dependent process illustrating the importance of exogenous cholera toxin (CT) in NHU cell culture. Taken together, this study presents evidence that PGDH functions in differentiated human urothelium to degrade PGE2 whose accumulation compromises mitotic quiescence, a characteristic feature of human urothelium in situ.