Systematic review to compare urothelium differentiation with urethral epithelium differentiation in fetal development, as a basis for tissue engineering of the male urethra

Abstract

Background: Tissue-engineered (TE) urethra is desirable in men with urethral disease (stricture or hypospadias) and shortage of local tissue. Although ideally a TE graft would contain urethral epithelium cells, currently, bladder epithelium (urothelium) is widely used, but morphologically different. Understanding the differences and similarities of urothelium and urethral epithelium could help design a protocol for in vitro generation of urethral epithelium to be used in TE grafts for the urethra. Purpose: To understand the development toward urethral epithelium or urothelium to improve TE of the urethra. Methods: A literature search was done following PRISMA guidelines. Articles describing urethral epithelium and bladder urothelium development in laboratory animals and humans were selected. Results: Twenty-nine studies on development of urethral epithelium and 29 studies on development of urothelium were included. Both tissue linings derive from endoderm and although adult urothelium and urethral epithelium are characterized by different gene expression profiles, the signaling pathways underlying their development are similar, including Shh, BMP, Wnt, and FGF. The progenitor of the urothelium and the urethral epithelium is the early fetal urogenital sinus (UGS). The urethral plate and the urothelium are both formed from the p63+ cells of the UGS. Keratin 20 and uroplakins are exclusively expressed in urothelium, not in the urethral epithelium. Further research has to be done on unique markers for the urethral epithelium. Conclusion: This review has summarized the current knowledge about embryonic development of urothelium versus urethral epithelium and especially focuses on the influencing factors that are potentially specific for the eventual morphological differences of both cell linings, to be a basis for developmental or tissue engineering of urethral tissue.