Ureterovesical junction: a stem cell niche for ureteral urothelial renewal and bladder urothelial injury repair

Epithelial stem cells are essential for lineage specification, tissue renewal, and regeneration. Here we show that ureterovesical junction (UVJ) of urinary tract harbors a major cluster of label-retaining urothelial cells that exhibit organoid-forming activities. During lineage-tracing, these Foxa2-expressing UVJ urothelial cells renew ureteral urothelium, but do not migrate into the bladder during homeostasis or mild bladder injury. Upon mechanical and chemical denudation of bladder urothelium, UVJ cells migrate rapidly into the bladder to replace bladder urothelium. This reepithelization also occurs during combination chemotherapies and severe bladder infection. Common to these injury repair processes is the early-phase and selective phosphorylation of TRKA and AKT which drives urothelial proliferation and differentiation. Nascent bladder urothelial cells derived from UVJ express both UVJ and bladder urothelial markers, signifying active remodeling influenced by intrinsic and extrinsic factors. Modulating the activities of UVJ cells may enhance bladder urothelial regeneration and combat challenging bladder diseases. The authors identified a major cluster of urothelial stem cells at the ureter-bladder junction. These cells efficiently formed colonies and organoids, and they renew ureteral urothelium and repair severe bladder urothelial injuries.