In vivo replacement of damaged bladder urothelium by Wolffian duct epithelial cells

The bladder’s remarkable regenerative capacity in response to injury had been thought to reside exclusively in its basal and intermediate cells. While examining consequences of DNA methyltransferase 1 (Dnmt1) inactivation in mouse embryonic bladder epithelium, we made the surprising discovery that Wolffian duct epithelial cells also support bladder regeneration. Conditional inactivation of Dnmt1 in mouse urethral and bladder epithelium triggered widespread apoptosis, depleted basal and intermediate bladder cells and disrupted Uroplakin protein expression. These events coincided with recruitment of Wolffian duct epithelial cells into Dnmt1 mutant urethra and bladder where they were reprogrammed to express bladder markers including FOXA1, Keratin 5, P63 and Uroplakin. This is the first evidence that Wolffian duct epithelial cells can be summoned in vivo to replace damaged bladder epithelium and function as a cell reservoir for bladder regeneration.