In vitro branching tubulogenesis: implications for developmental and cystic disorders, nephron number, renal repair, and nephron engineering.

Branching tubulogenesis of the ureteric bud is critically important for kidney development. Recent findings using three-dimensional cell culture systems for in vitro branching tubulogenesis are likely to shed light on the mechanisms of ureteric bud morphogenesis. Here, we try to unify these findings with those obtained using genetic approaches and organ culture of the embryonic kidney into a working model of ureteric bud branching tubulogenesis. It appears that the balance between branching tubulogenesis facilitating growth factors such as epidermal growth factor receptor ligands, hepatocyte growth factor, insulin-like growth factors, and inhibitory growth factors such as transforming growth factor beta family members may regulate branching morphogenesis. Growth factors induce epithelial cell proliferation, migration, and modulate the expression of a variety of proteins. Downstream in the growth factor-mediated tubulogenesis pathway, extracellular proteases, protease inhibitors, extracellular matrix proteins, and integrins are likely to act as effectors and regulators of branching tubulogenesis. Discussed in some detail are the relevance of insights gleaned from in vitro models of branching tubulogenesis to congenital urogenital abnormalities, cystic kidney diseases, oligonephropathies and hypertension, tubular cell regeneration after injury, and tubular engineering.