Koushik K Das1,2,3,4, Steffen Heeg1,2,3,5, Jason R Pitarresi1,2,3, Maximilian Reichert1,2,3,6, Basil Bakir1,2,3, Shigetsugu Takano1,2,3, Janel L Kopp7, Anja Wahl-Feuerstein5, Philip Hicks1,2,3, Maike Sander8, Anil K Rustgi1,2,3,9. 1. Division of Gastroenterology, University of Pennsylvania, Philadelphia, Pennsylvania. 2. Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. 3. Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania. 4. Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri. 5. Department of Medicine II, Medical Center, University of Freiburg, Freiburg, Germany. 6. II. Medizinische Klinik, Technical University of Munich, Munich, Germany. 7. Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, Canada. 8. Department of Pediatrics, Department of Cellular and Molecular Medicine, University of California San Diego School of Medicine, San Diego, California. 9. Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
Abstract
BACKGROUND: The plasticity of pancreatic acinar cells to undergo acinar to ductal metaplasia (ADM) has been demonstrated to contribute to the regeneration of the pancreas in response to injury. Sox9 is critical for ductal cell fate and important in the formation of ADM, most likely in concert with a complex hierarchy of, as yet, not fully elucidated transcription factors. RESULTS: By using a mouse model of acute pancreatitis and three dimensional organoid culture of primary pancreatic ductal cells, we herein characterize the Ets-transcription factor Etv5 as a pivotal regulator of ductal cell identity and ADM that acts upstream of Sox9 and is essential for Sox9 expression in ADM. Loss of Etv5 is associated with increased severity of acute pancreatitis and impaired ADM formation leading to delayed tissue regeneration and recovery in response to injury. CONCLUSIONS: Our data provide new insights in the regulation of ADM with implications in our understanding of pancreatic homeostasis, pancreatitis and epithelial plasticity. Developmental Dynamics 247:854-866, 2018.
BACKGROUND: The plasticity of pancreatic acinar cells to undergo acinar to ductal metaplasia (ADM) has been demonstrated to contribute to the regeneration of the pancreas in response to injury. Sox9 is critical for ductal cell fate and important in the formation of ADM, most likely in concert with a complex hierarchy of, as yet, not fully elucidated transcription factors. RESULTS: By using a mouse model of acute pancreatitis and three dimensional organoid culture of primary pancreatic ductal cells, we herein characterize the Ets-transcription factor Etv5 as a pivotal regulator of ductal cell identity and ADM that acts upstream of Sox9 and is essential for Sox9 expression in ADM. Loss of Etv5 is associated with increased severity of acute pancreatitis and impaired ADM formation leading to delayed tissue regeneration and recovery in response to injury. CONCLUSIONS: Our data provide new insights in the regulation of ADM with implications in our understanding of pancreatic homeostasis, pancreatitis and epithelial plasticity. Developmental Dynamics 247:854-866, 2018.
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