Urothelial generation and regeneration in development, injury, and cancer

Abstract

Homeostatic maintenance and repair of the urothelium upon injury are required for a functional bladder in both healthy and disease conditions. Understanding the cellular and molecular mechanisms underlying the urothelial regenerative response is key to designing strategies for tissue repair and ultimately treatments for urologic diseases including urinary tract infections, voiding dysfunction, painful bladder syndrome, and bladder cancer. In this article, we review studies on urothelial ontogeny during development and regeneration following various injury modalities. Signaling pathways involved in urothelial regeneration and in urothelial carcinogenesis are also discussed. Developmental Dynamics 246:336-343, 2017. © 2016 Wiley Periodicals, Inc.

Keywords: Uropathogenic E. coli; urinary tract infections; retinoic acid; BMP4; bladder; progenitor cells; regeneration; stem cells.

Figure 1. Schematic view of urothelial cell layers, regulatory pathways important for urothelial proliferation, differentiation, and regeneration upon injury

(A–B). Urothelial cells and markers (C). Bmp4 is expressed in the mesenchymal compartment and signals to the urothelium through its receptor, BmpR1a to regulate proliferation and terminal differentiation status. Estrogen can regulate urothelial regeneration through regulating Bmp4 pathway directly or indirectly by downregulating the cytokine, Interleukin-6. Retinoic acid and Wnt signaling govern urothelial regeneration by regulating genes such as Bmp4. (D). During a UTI, uropathogenic E. coli invade and rapidly replicate inside superficial cells. Then the host tissue responds by exfoliating the damaged superficial cell layer and recruiting neutrophils and monocytes/macrophages to clear the infection. The urothelium mounts a rapid proliferative and regenerative response to reestablish the barrier.