Shannon Glaser1, Fanyin Meng2, Yuyan Han3, Paolo Onori4, Billy K Chow5, Heather Francis2, Julie Venter3, Kelly McDaniel6, Marco Marzioni7, Pietro Invernizzi8, Yoshiyuki Ueno9, Jia-ming Lai10, Li Huang10, Holly Standeford6, Domenico Alvaro11, Eugenio Gaudio4, Antonio Franchitto12, Gianfranco Alpini13. 1. Research, Central Texas Veterans Health Care System, Temple, Texas; Scott & White Digestive Disease Research Center, Scott & White, Temple, Texas; Department of Medicine, Division of Gastroenterology, Texas A&M Health Science Center College of Medicine, Temple, Texas. 2. Research, Central Texas Veterans Health Care System, Temple, Texas; Scott & White Digestive Disease Research Center, Scott & White, Temple, Texas; Department of Medicine, Division of Gastroenterology, Texas A&M Health Science Center College of Medicine, Temple, Texas; Academic Operations, Scott & White, Temple, Texas. 3. Department of Medicine, Division of Gastroenterology, Texas A&M Health Science Center College of Medicine, Temple, Texas. 4. Department of Anatomical, Histological, Forensic Medicine, and Orthopedics Sciences, Sapienza, Rome, Italy. 5. School of Biological Sciences, The University of Hong Kong, Hong Kong, China. 6. Research, Central Texas Veterans Health Care System, Temple, Texas. 7. Department of Medicine, Universita' Politecnica delle Marche, Ancona, Italy. 8. Liver Unit and Center for Autoimmune Liver Diseases, Humanitas Clinical and Research Center, Rozzano, Milan, Italy. 9. Division of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata, Japan. 10. Department of Hepatobiliary Surgery, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. 11. Department of Medico-Surgical Sciences and Biotechnologies, Polo Pontino, Italy. 12. Department of Anatomical, Histological, Forensic Medicine, and Orthopedics Sciences, Sapienza, Rome, Italy; Eleonora Lorillard Spencer Cenci Foundation, Rome, Italy. 13. Research, Central Texas Veterans Health Care System, Temple, Texas; Scott & White Digestive Disease Research Center, Scott & White, Temple, Texas; Department of Medicine, Division of Gastroenterology, Texas A&M Health Science Center College of Medicine, Temple, Texas. Electronic address: galpini@tamu.edu.
Abstract
BACKGROUND & AIMS: Proliferating cholangiocytes secrete and respond to neuroendocrine hormones, including secretin. We investigated whether secretin secreted by S cells and cholangiocytes stimulates biliary proliferation in mice. METHODS: Cholestasis was induced in secretin knockout (Sct(-/-)) and wild-type (control) mice by bile duct ligation (BDL). At days 3 and 7 after BDL, control and Sct(-/-) mice received tail-vein injections of morpholinos against microRNA 125b or let7a. One week later, liver tissues and cholangiocytes were collected. Immunohistochemical, immunoblot, luciferase reporter, and real-time polymerase chain reaction assays were performed. Intrahepatic bile duct mass (IBDM) and proliferation were measured. Secretin secretion was measured in conditioned media from cholangiocytes and S cells and in serum and bile. RESULTS: Secretin secretion was increased in supernatants from cholangiocytes and S cells and in serum and bile after BDL in control mice. BDL Sct(-/-) mice had lower IBDM, reduced proliferation, and reduced production of vascular endothelial growth factor (VEGF) A and nerve growth factor (NGF) compared with BDL control. BDL and control mice given morpholinos against microRNA 125b or let7a had increased IBDM. Livers of mice given morpholinos against microRNA 125b had increased expression of VEGFA, and those treated with morpholinos against microRNA let7a had increased expression of NGF. Secretin regulated VEGF and NGF expression that negatively correlated with microRNA 125b and let7a levels in liver tissue. CONCLUSIONS: After liver injury, secretin produced by cholangiocytes and S cells reduces microRNA 125b and let7a levels, resulting in up-regulation of VEGF and NGF. Modulation of cholangiocyte expression of secretin could be a therapeutic approach for biliary diseases.
BACKGROUND & AIMS: Proliferating cholangiocytes secrete and respond to neuroendocrine hormones, including secretin. We investigated whether secretin secreted by S cells and cholangiocytes stimulates biliary proliferation in mice. METHODS:Cholestasis was induced in secretin knockout (Sct(-/-)) and wild-type (control) mice by bile duct ligation (BDL). At days 3 and 7 after BDL, control and Sct(-/-) mice received tail-vein injections of morpholinos against microRNA 125b or let7a. One week later, liver tissues and cholangiocytes were collected. Immunohistochemical, immunoblot, luciferase reporter, and real-time polymerase chain reaction assays were performed. Intrahepatic bile duct mass (IBDM) and proliferation were measured. Secretin secretion was measured in conditioned media from cholangiocytes and S cells and in serum and bile. RESULTS:Secretin secretion was increased in supernatants from cholangiocytes and S cells and in serum and bile after BDL in control mice. BDL Sct(-/-) mice had lower IBDM, reduced proliferation, and reduced production of vascular endothelial growth factor (VEGF) A and nerve growth factor (NGF) compared with BDL control. BDL and control mice given morpholinos against microRNA 125b or let7a had increased IBDM. Livers of mice given morpholinos against microRNA 125b had increased expression of VEGFA, and those treated with morpholinos against microRNA let7a had increased expression of NGF. Secretin regulated VEGF and NGF expression that negatively correlated with microRNA 125b and let7a levels in liver tissue. CONCLUSIONS: After liver injury, secretin produced by cholangiocytes and S cells reduces microRNA 125b and let7a levels, resulting in up-regulation of VEGF and NGF. Modulation of cholangiocyte expression of secretin could be a therapeutic approach for biliary diseases.
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