The urinary bladder is lined by a transitional urothelium with nonnally slow tumover but substantial injuiyinducible regenerative capacity. Tlie urothelial stem cell (USC) niche, comprising basal stem cells and underlying mesenchyme, fuels the renewal. However, little is known about the molecular features ofthe USCs or the regulatory mechanisms goveming USC niche adaptation in injury or disease. The long term objectives of the research program is to identify the genes, pathways and molecules that govem the rapid, injuryinduced regenerative response of normally quiescent urothelial stem cells (USCs) and to apply what we leam about the nonnal mechanisms to shed light on disease processes with abnormal urothelial tumover (e.g., interstitial cystitis/painful bladder syndrome, bladder cancer). We have developed and study two models of injury, one caused by infection by uropathogenic E. coli (UPEC), the primary causative agent of urinary tract infections (UTIs), and the other by a chemical, protamine sulfate (PS). We show that acute UPEC infection results ui rapid sloughing of superficial cells lining the bladder, marked acute inflammatory response, and a substantial spike in mitotic activity of the USC niche. On the other hand, chemical injury induced by PS causes sloughing but no inflammation and no USC response. We find that epithelial renewal following infectious injury is mediated by the Bone moiphogenetic protein (Bmp) signaling pathway. Inducible cre-recombinase-mediated ablation of the Bmp4 receptor Bmprla in the bladder epithelium resulted in its inability to sustain USC proliferation or regenerate terminally differentiated superficial cells in response to infection. Furthermore, long term infection led to a disruption of epitheUalmesenchymal boundaries and features of qjithelial-to-mesenchymal transition.
The specific aims of this application are to elucidate the mechanism tmderlying urothelial response to acute and long term UPEC infection in Bmp4- signaling deficient mice and to elucidate the cellular and molecular underpinnings ofthe urothelial responses to different forms of injury.
This proposal will establish systems to study how the urinary bladder repairs and renews itself following injury. TTiis work should be of tremendous value and interest to improve techniques to regenerate bladder tissue in vivo or ex vivo for patients whose bladders have been lost or damaged due to disease and have climcai significance for other major chronic bladder disorders: interstitial cystitis and bladder cancer.
