Figure 10.

Diagram of proposed actions of keratinocyte growth factor (KGF) versus PBS after cyclophosphamide administration. Left panel: Uninjured: diagram of different cell types in the uninjured urothelium [basal cell (B cell), intermediate cell (I cell), and superficial cell (S cell)]. Middle panel: PBS: cyclophosphamide (CPP) is metabolized to acrolein (Acr), leading to acute injury from 2 hours to 1 day, including superficial cell necrosis and intermediate and basal cell apoptosis. During early regeneration (1 to 3 days), KRT14⁺ basal cells proliferate to begin reconstituting intermediate cells, but superficial cells remain absent. During late regeneration (10 to 28 days), KRT14⁺ cells begin to regress, with reduced proliferation, and other urothelial layers are more intact, including partial regeneration of superficial cells. Right panel: KGF: during acute injury (2 hour to 1 day), KGF pretreatment does not prevent superficial cell necrosis, but blocks intermediate and basal cell apoptosis by driving AKT downstream of fibroblast growth factor receptor 2 (FGFR2). During early regeneration, KGF pretreatment leads to an early burst of KRT5⁺ (only) cell proliferation (starting at 6 hours) and leads to early regeneration of superficial cells (from reduced injury and/or the KRT5⁺ cell proliferative burst). During late regeneration, KGF pretreatment leads to nearly full restoration of urothelial layers, including the absence of proliferating KRT14⁺ cells (although small patches of nonproliferating KRT14⁺ basal cells persist). ERK, extracellular signal-regulated kinase; UPK3, uroplakin 3a.