Abstract

Summary Autosomal recessive polycystic kidney disease (ARPKD) is a pediatric genetic nephropathy caused by mutations in PKHD1, which encodes fibrocystin. The cellular basis and epithelial dynamics of cyst formation remain incompletely understood. We used lineage-tracing systems in rat and mouse to define epithelial behavior during cystogenesis. Clonal labeling revealed that renal and biliary epithelial cells undergo marked expansion as cysts form. Genetic mosaic analysis showed that individual Pkhd1-deficient cholangiocytes can generate millimeter-scale cysts within one year. Mathematical modeling demonstrated that biliary epithelial proliferation alone can account for cyst growth to millimeter size within weeks to months, depending on initial cell number and doubling time. Transcriptomic profiling of early cystic liver identified upregulated cell-cycle regulators, including CDK1. Pharmacological CDK1 inhibition attenuated fibrocystic liver disease in vivo. These findings show that epithelial cell expansion is the primary driver of cystogenesis and loss of fibrocystin activates a pro-proliferative program that can be therapeutically targeted.