KRT7 CreER 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/G551Dmutation. Following tamoxifen induction, KRT7-derived EGFP⁺ cells were identified in glandular and ductal epithelia across multiple organs. Pulse-chase lineage tracing revealed that KRT7⁺BSND⁺ 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.