<i>De novo</i> formation of tuft and goblet cells protects the intrapancreatic biliary duct system from inflammatory injury

The biliary tree is susceptible to inflammatory injury that can result in severe liver damage. However, the intrapancreatic biliary duct system is largely refractory to damage caused by pancreatitis; the mechanisms that protect these ducts from injury remain unknown. Here, we demonstrate that, although serine/threonine-protein kinase DCLK1 (DCLK1) + tuft cells and mucin-2 (MUC2) + goblet cells were largely restricted to the ampulla of non-injured mice, they exhibited a marked increase in the ampulla and a progressive appearance in the intrapancreatic biliary duct system after injury. The increase in goblet cells was transient and induced upon successive incidence of injury. In contrast, tuft cells persisted in the ductal system and transiently expressed proopiomelanocortin after injury. Mice lacking this tuft and goblet cell response exhibited fibrotic scarring of the ducts and diminished cholangiocyte regeneration. Lineage tracing demonstrated that tuft and goblet cells in the intrapancreatic biliary duct system do not originate from acinar cells, suggesting that tuft cells in the intrapancreatic duct system are derived from a unique progenitor cell, separate from those found in the pancreatic parenchyma after injury. Similar to tuft and goblet cells derived from neighboring leucine-rich repeat-containing G-protein coupled receptor 5 (Lgr5) + stem cells in the small intestine, levels of tuft cells in the ampulla and intrapancreatic biliary ducts are dependent on the activity of the bromodomain and extra-terminal domain (BET) family of chromatin adaptors, and the hyperplastic response of both tuft and goblet cells requires interleukin-4 receptor subunit alpha (IL4RA) signaling. Taken together, our results demonstrate a role for tuft and goblet cells in the acute and long-term monitoring of the intrapancreatic biliary duct system.