Hierarchical transcriptional profile of urothelial cells development and differentiation

- A hierarchy of transcription factor profile is proposed for urothelial cell differentiation.
- The transcription factor KLF5 resides at the top of the hierarchy followed by PPAR-γ.
- Uroplakins are regulated by a set of transcription factors including but not limited to GATA4, FOXA1 and GRHL3.

The urothelial lining of the lower urinary tract is the most efficient permeability barrier in animals, exhibiting a highly differentiated phenotype and a remarkable regenerative capacity upon wounding. During development and possibly during repair, cells undergo a sequence of hierarchical transcriptional events that mark the transition of these cells from the least differentiated urothelial phenotype characteristic of the basal cell layer, to the most differentiated cellular phenotype characteristic of the superficial cell layer. Unraveling normal urothelial differentiation program is essential to uncover the underlying causes of many congenital abnormalities and for the development of an appropriate differentiation niche for stem cells, for future use in urinary tract tissue engineering and organ reconstruction. Kruppel like factor-5 appears to be at the top of the hierarchy activating several downstream transcription factors, the most prominent of which is peroxisome proliferator activator receptor-γ. Eventually those lead to the activation of transcription factors that directly regulate the expression of uroplakin proteins along with other proteins that mediate the permeability function of the urothelium.In this review, we discuss the most recent findings in the area of urothelial cellular differentiation and transcriptional regulation, aiming for a comprehensive overview that aids in a refined understanding of this process.