The integrity and function of the exocrine pancreas depends on Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) expression in acinar cells.
Final Report Abstract
Impaired cystic fibrosis transmembrane conductance regulator (CFTR) function is associated with cystic fibrosis (CF), characterized by pancreatic insufficiency. There is a clear association between CFTR gene mutations and idiopathic chronic pancreatitis (CP) or alcohol-induced disease. Although the pathology of pancreatic disease in CF has been well characterized, the mechanisms leading to pancreatic destruction are less well understood. One postulated mechanism is low flow and a high protein concentration which leads to hyperviscous mucus which precipitates in the duct lumen blocking ducts, destroys acinar tissue, which is replaced by fibrotic tissue over time. A number of murine cystic fibrosis models have been developed using different gene-targeting strategies which express no or mutated protein. Interestingly, the mice showed mild effects in the lungs and the pancreas but suffer frequently from intestinal abnormalities and obstruction. Through the generation and characterization of pancreasspecific and cell type-specific Cftr deletion models, we have demonstrated that loss of CFTR function impairs pancreatic regeneration following acute injury. Using a combination of histological analysis, three-dimensional imaging, and single-cell RNA sequencing, we identified distinct regenerative effects depending on the targeted compartment. While acinarspecific Cftr deletion did not substantially worsen regeneration after AP, ductal-specific Cftr deletion resulted in profound loss of acinar tissue, persistent ductal proliferation, and transcriptional activation of stress and proliferation pathways. These findings provide mechanistic insights into how CFTR dysfunction in non-CF individuals might contribute to the risk of pancreatitis and pancreatic carcinogenesis.
Publications
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Isolation of single cells from healthy and diseased murine pancreas from early and late-stage cancer models. Pancreatology, 24, e63.
Chhabra, Nirav; Einwächter, Henrik & Schmid, Roland M.
