Single-cell transcriptome analysis defines heterogeneity of the murine pancreatic ductal tree

Hendley, Audrey M; Rao, Arjun A; Leonhardt, Laura; Ashe, Sudipta; Smith, Jennifer A; Giacometti, Simone; Peng, Xianlu L; Jiang, Honglin; Berrios, David I; Pawlak, Mathias; Li, Lucia Y; Lee, Jonghyun; Collisson, Eric A; Anderson, Mark S; Fragiadakis, Gabriela K; Yeh, Jen Jen; Ye, Chun Jimmie; Kim, Grace E; Weaver, Valerie M; Hebrok, Matthias

To study disease development, an inventory of an organ's cell types and understanding of physiologic function is paramount. Here, we performed single-cell RNA-sequencing to examine heterogeneity of murine pancreatic duct cells, pancreatobiliary cells, and intrapancreatic bile duct cells. We describe an epithelial-mesenchymal transitory axis in our three pancreatic duct subpopulations and identify osteopontin as a regulator of this fate decision as well as human duct cell dedifferentiation. Our results further identify functional heterogeneity within pancreatic duct subpopulations by elucidating a role for geminin in accumulation of DNA damage in the setting of chronic pancreatitis. Our findings implicate diverse functional roles for subpopulations of pancreatic duct cells in maintenance of duct cell identity and disease progression and establish a comprehensive road map of murine pancreatic duct cell, pancreatobiliary cell, and intrapancreatic bile duct cell homeostasis.