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Abstract: PO2279

Keratin 5+ Urothelial Cells Are Developmental and Tissue Repair Progenitors in the Bladder

Session Information

Category: Pediatric Nephrology

  • 1700 Pediatric Nephrology

Authors

  • Jackson, Ashley R., Center for Clinical and Translational Research, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States
  • Li, Birong, Center for Clinical and Translational Research, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States
  • Becknell, Brian, Center for Clinical and Translational Research, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States
Background

Urothelium is nearly quiescent during homeostasis, but injury engages a robust regenerative capacity. Several progenitor cell candidates have been implicated, but prevailing models demonstrate conflicting roles discrete urothelial subpopulations. We recently demonstrated that Keratin 5 (K5)-expressing UCs are temporally restricted renal urothelium progenitors. It is unclear whether similar temporal restrictions are imposed on bladder K5-UCs, and whether an investigation into the temporality of the K5-UC progenitor may clarify bladder progenitor models. The objective of this study was to determine temporal progenitor-progeny relationships responsible for bladder urothelium generation and regeneration.

Methods

Using Krt5CreERT2;RosatdT mice, K5-UCs were inducibly and permanently labeled with tdTomato (tdT). Tamoxifen (TMX) was administered at postnatal day (P)1, P7, P14, P21 or P41. Mice were sacrificed (SAC) at P42 or subjected to a single round of urothelial injury (cyclophosphamide) and euthanized 2 weeks later. Immunofluorescence microscopy was used to visualize and quantitate tdT, K5, (uroplakin), Upk and K20 expression.

Results

Fate mapping analysis found that 22% (TMXP1-SACP42) and 23.5% (TMXP7-SACP42) of neonatal tdTK5 UCs differentiated into adult Upk+ UCs (tdTK5+;Upk+, mostly intermediate cells) by P42 compared to 9% (TMXP14-SACP42) or 2.25% (TMXP21-SACP42) of juvenile tdTK5 UCs, and 0% adult (TMXP42-SACP56) (P<0.01, ANOVA). Following urothelial injury, 63% (TMXP7-CycP42), 54.33% (TMXP14-CycP42) and 69% (TMXP21-CYCP42) of umbrella cells expressed tdTK5 (tdTK5+;K5-;Upk+;K20+). Adult (TMXP41-CYCP42 & TMXP35-CYCP42) tdTK5 UCs rarely formed umbrella cells.

Conclusion

K5-UCs form intermediate and superficial cells, but the capacity for K5-UCs to form these derivatives is lost over time. In response to acute adult bladder urothelium injury, neonatal and juvenile tdTK5+ UCs regenerate umbrella cells, while adult tdTK5+ UCs did not. These studies establish that bladder K5-UCs are context dependent progenitors - responsive to temporal and pathologic cues. Our findings support an intermediate cell acute injury progenitor model, and show that intermediate cells formed by neonatal and juvenile K5-UCs repair acutely injured bladder urothelium.

Funding

  • NIDDK Support