4.8 Article

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

Publisher

NATL ACAD SCIENCES
DOI: 10.1073/pnas.1802966115

Keywords

bladder; Wolffian duct; DNMT1; apoptosis; regeneration

Funding

  1. National Institutes of Health [R01 DK099328, U54 DK104310, U01 DK110807, U54 DK104309, R01 DK095044-03]
  2. NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [U01DK110807, U54DK104309, R01DK095044, U54DK104310, R01DK099328] Funding Source: NIH RePORTER

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The bladder's remarkable regenerative capacity had been thought to derive exclusively from its own progenitors. While examining consequences of DNA methyltransferase 1 (Dnmt1) inactivation in mouse embryonic bladder epithelium, we made the surprising discovery that Wolffian duct epithelial cells can support bladder regeneration. Conditional Dnmt1 inactivation in mouse urethral and bladder epithelium triggers widespread apoptosis, depletes basal and intermediate bladder cells, and disrupts uroplakin protein expression. These events coincide with Wolffian duct epithelial cell recruitment into Dnmt1 mutant urethra and bladder where they are reprogrammed to express bladder markers, including FOXA1, keratin 5, P63, and uroplakin. This is evidence that Wolffian duct epithelial cells are summoned in vivo to replace damaged bladder epithelium and function as a reservoir of cells for bladder regeneration.

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