Title: The MET Receptor Tyrosine Kinase Confers Repair of Murine Pancreatic Acinar Cells following Acute and Chronic Injury.
Authors: Gaziova, Ivana; Jackson, Daniel; Boor, Paul J; Carter, Dwayne; Cruz-Monserrate, Zobeida; Elferink, Cornelis J; Joshi, Aditya D; Kaphalia, Bhupendra; Logsdon, Craig D; Pereira de Castro, Karen; Soong, Lynn; Tao, Xinrong; Qiu, Suimin; Elferink, Lisa A
Published In PLoS One, (2016)
Abstract: Acinar cells represent the primary target in necroinflammatory diseases of the pancreas, including pancreatitis. The signaling pathways guiding acinar cell repair and regeneration following injury remain poorly understood. The purpose of this study was to determine the importance of Hepatocyte Growth Factor Receptor/MET signaling as an intrinsic repair mechanism for acinar cells following acute damage and chronic alcohol-associated injury. Here, we generated mice with targeted deletion of MET in adult acinar cells (MET-/-). Acute and repetitive pancreatic injury was induced in MET-/- and control mice with cerulein, and chronic injury by feeding mice Lieber-DeCarli diets containing alcohol with or without enhancement of repetitive pancreatic injury. We examined the exocrine pancreas of these mice histologically for acinar death, edema, inflammation and collagen deposition and changes in the transcriptional program. We show that MET expression is relatively low in normal adult pancreas. However, MET levels were elevated in ductal and acinar cells in human pancreatitis specimens, consistent with a role for MET in an adaptive repair mechanism. We report that genetic deletion of MET in adult murine acinar cells was linked to increased acinar cell death, chronic inflammation and delayed recovery (regeneration) of pancreatic exocrine tissue. Notably, increased pancreatic collagen deposition was detected in MET knockout mice following repetitive injury as well alcohol-associated injury. Finally, we identified specific alterations of the pancreatic transcriptome associated with MET signaling during injury, involved in tissue repair, inflammation and endoplasmic reticulum stress. Together, these data demonstrate the importance of MET signaling for acinar repair and regeneration, a novel finding that could attenuate the symptomology of pancreatic injury.
PubMed ID: 27798657
MeSH Terms: Acinar Cells/enzymology*; Acinar Cells/pathology*; Acute Disease; Alcohol Drinking/pathology; Animals; Ceruletide; Chronic Disease; Collagen/metabolism; Disease Models, Animal; Gene Deletion; Humans; Inflammation/pathology; Macrophages/metabolism; Macrophages/pathology; Mice, Inbred C57BL; Pancreas/enzymology*; Pancreas/injuries*; Pancreas/pathology; Pancreatitis, Chronic/enzymology; Pancreatitis, Chronic/pathology; Proto-Oncogene Proteins c-met/metabolism*; Regeneration; Wound Healing*