KRT7CreER Ferrets Enable Lineage Tracing of Ductal Epithelia and Pancreatic Remodeling

Abstract

Keratin 7 (KRT7) is expressed in simple and ductal epithelia and is associated with epithelial plasticity during development, injury, and disease. However, the in vivo fate and regenerative behavior of KRT7 cells remain poorly defined because lineage-tracing models are lacking in species that closely recapitulate human disease. To address this gap, we generated KRT7CreER ferrets and crossed them with ROSAmTmG Cre-reporter ferrets, with or without the CFTRG551D/G551D mutation. Following tamoxifen induction, KRT7-derived EGFP cells were identified in glandular and ductal epithelia across multiple organs. Pulse-chase lineage tracing revealed that KRT7BSND cells turn over rapidly during salivary gland development. In the pancreas, KRT7 lineage-labeled cells are present at all levels of the ductal tree under homeostatic conditions. In cystic fibrosis (CF) ferrets, KRT7-derived centroacinar cells and intercalated ductal lineages persisted and underwent marked remodeling, characterized by expansion of the SOX9 centroacinar cell pod into intercalated ducts. Although acinar cells were not lineage-labeled in the healthy pancreas, EGFP/CELA3B cells emerged in the CF pancreas and in acinar-derived organoids, consistent with induction of KRT7 during acinar-to-ductal metaplasia. These findings establish KRT7CreER ferrets as a versatile model for studying ductal epithelial lineage dynamics, pancreatic remodeling, and epithelial plasticity in both homeostatic and pathological conditions.