Abstract
Chronic pancreatitis, a known risk factor for the development of pancreatic ductal adenocarcinoma (PDA), is a serious, widespread medical condition characterized by inflammation, fibrosis, and acinar to ductal metaplasia (ADM). ADM is a cell type transdifferentiation event where pancreatic acinar cells become ductal-like under conditions of injury or oncogenic mutation. Here, we show that chronic pancreatitis and ADM in genetically wild type mice results in the formation of a significant population of chemosensory tuft cells. Transcriptomic analyses of pancreatitis tuft cells identify expression of inflammatory mediators, consistent with a role for tuft cells in injury progression and/or resolution. Though similar to tuft cell populations in other organs and disease systems, we identified a number of key differences that suggest context-specific tuft cell functions. We evaluated seven different mouse strains for tuft cell formation in response to chronic injury and identified significant heterogeneity reflecting varying proclivity for epithelial plasticity between strains. These results have interesting implications in the role of epithelial plasticity and heterogeneity in pancreatitis and highlight the importance of mouse strain selection when modeling human disease.
Highlights
Pancreatitis, the third leading cause of gastrointestinal-related hospitalizations, is a serious medical condition characterized by inflammation of the exocrine pancreas
Tuft cell formation is characteristic of a portion of human pancreatitis cases and has been shown in multiple mouse models of tissue injury in several gastrointestinal organs (SaquiSalces et al, 2011; Delgiorno et al, 2014)
We found that prolonged caerulein treatment resulted in acinar cell loss and an increase in acinar to ductal metaplasia (ADM), stromal deposition, and mucin expression (Supplementary Figure S1)
Summary
Pancreatitis, the third leading cause of gastrointestinal-related hospitalizations, is a serious medical condition characterized by inflammation of the exocrine pancreas. Pancreatitis presents in either an acute or chronic form. In its chronic form, pancreatitis is characterized by persistent inflammation, fibrosis, and acinar cell metaplasia and results in permanent pancreatic damage (Murtaugh and Keefe, 2015). Repeated episodes of acute pancreatitis can progress to chronic pancreatitis. While both forms carry a risk of mortality, they can lead to other serious conditions. Chronic pancreatitis is a known risk factor for pancreatic ductal adenocarcinoma (PDA), currently the third-most common cause of cancer-related death in the United States (Pinho et al, 2014; Siegel et al, 2019)
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