Pancreas-Specific Ablation of β1 Integrin Induces Tissue Degeneration by Disrupting Acinar Cell Polarity

Background & Aims: Integrin contact with basement membrane is a major determinant of epithelial cell polarity. β1 integrin heterodimers are the primary receptors for basement membrane in pancreatic acinar cells, which function to synthesize and directionally secrete digestive enzymes into a central lumen. Aberrant acinar secretion and exposure of the parenchyma to digestive enzyme activity lead to organ damage and pancreatitis. Methods: β1 integrin conditional knockout mice were crossed to Ptf1a-Cre mice to ablate β1 integrin in the pancreas. Histopathology of aged and cerulein-treated mice were assessed by histology and immunocytochemistry. Directional secretion was determined in vitro by FM1-43 loading with cerulein stimulation. Results: Pancreas-specific ablation of β1 integrin led to progressive organ degeneration, associated with focal acinar cell necrosis and ductal metaplasia along with widespread inflammation and collagen deposition. β1 Integrin-null pancreata were highly susceptible to cerulein-induced acute pancreatitis, displaying an enhanced level of damage with no loss in regeneration. Degenerating β1 integrin-null pancreata were marked by disruption of acinar cell polarity. Protein kinase C ε, normally localized apically, was found in the cytoplasm where it can lead to intracellular digestive enzyme activation. β1 Integrin-null acinar cells displayed indiscriminate secretion to all membrane surfaces, consistent with an observed loss of basolateral membrane localization of Munc18c, which normally prevents basal secretion of digestive enzymes. Conclusions: Ablation of β1 integrin induces organ atrophy by disrupting acinar cell polarity and exposing the pancreatic parenchyma to digestive enzymes.