Presented October 25th - 28th, 2007 at the 2007 Urological Research Society (URS) Meeting - Napa, California

Objective: While epithelial stem cells for skin, cornea and prostate have been identified, the urothelial stem cell has remained elusive. In other epithelia, the slow-cycling nature of stem cells has been utilized to identify them. Once an epithelial stem cell incorporates labeled nucleic acid, it retains that label in its DNA for longer periods of time than a cell that is proliferating, and is termed a "label-retaining cell (LRC)." Stem cells from different organ systems have also been shown to express high levels of specific marker proteins and to be more clonogenic than their more differentiated counterparts. Our goal was to identify urothelial stem cells.

Methods: We created urothelial LRCs by administering BrdU to juvenile rats. Bladders were harvested at different time points and analyzed with immunohistochemistry (IHC) and flow cytometry to determine the labeling index and protein expression of LRCs. Urothelium from labeled bladders was cultured to determine the proliferative ability of LRCs.

Results: IHC of the bladders demonstrated heavy incorporation of BrdU in the urothelium at early time points. One year after labeling, 9 % of basal cells still retained label. IHC localized Bcl, p63 and integrins in the basal compartment in or near LRCs but not uniquely in these cells. Flow cytometry demonstrated that LRCs were small, low granularity and uniquely and extremely β₄ integrin-bright. Cultured LRCs produced a significantly higher number of total colonies and large colonies.

Conclusions: LRCs in the bladder localize to the basal layer, are small, low granularity, β₄ integrin-rich, slow-cycling and demonstrate superior clonogenic and proliferative ability compared to more differentiated cells. We propose that LRCs represent a population of putative urothelial stem cells.

Authors: Kurzrock EA, Lieu DK, Chan CW and Isseroff RR

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