title: Serotonin promotes acinar dedifferentiation following pancreatitis-induced regeneration in the adult pancreas.
abstract: The exocrine pancreas exhibits a distinctive capacity for tissue regeneration and renewal following injury. This regenerative ability has important implications for a variety of disorders, including pancreatitis and pancreatic cancer, diseases associated with high morbidity and mortality. Thus, understanding its underlying mechanisms may help in developing therapeutic interventions. Serotonin has been recognized as a potent mitogen for a variety of cells and tissues. Here we investigated whether serotonin exerts a mitogenic effect in pancreatic acinar cells in three regenerative models, inflammatory tissue injury following pancreatitis, tissue loss following partial pancreatectomy, and thyroid hormone-stimulated acinar proliferation. Genetic and pharmacological techniques were used to modulate serotonin levels in vivo. Acinar dedifferentiation and cell cycle progression during the regenerative phase were investigated over the course of 2 weeks. By comparing acinar proliferation in the different murine models of regeneration, we found that serotonin did not affect the clonal regeneration of mature acinar cells. Serotonin was, however, required for acinar dedifferentiation following inflammation-mediated tissue injury. Specifically, lack of serotonin resulted in delayed up-regulation of progenitor genes and delayed the formation of acinar-to-ductal metaplasia and defective acinar cell proliferation. We identified serotonin-dependent acinar secretion as a key step in progenitor-based regeneration, as it promoted acinar cell dedifferentiation and the recruitment of type 2 macrophages. Finally, we identified a regulatory Hes1-Ptfa axis in the uninjured adult pancreas, activated by zymogen secretion. Our findings indicated that serotonin plays a critical role in the regeneration of the adult pancreas following pancreatitis by promoting the dedifferentiation of acinar cells.
authors.affiliation: Swiss Hepato-pancreato-biliary Centre, Department of Visceral and Transplantation Surgery, University Hospital, Zurich, Switzerland.
authors.forename: Enrica
authors.initials: E
authors.lastname: Saponara
authors.affiliation: Swiss Hepato-pancreato-biliary Centre, Department of Visceral and Transplantation Surgery, University Hospital, Zurich, Switzerland.
authors.forename: Kamile
authors.initials: K
authors.lastname: Grabliauskaite
authors.affiliation: Swiss Hepato-pancreato-biliary Centre, Department of Visceral and Transplantation Surgery, University Hospital, Zurich, Switzerland.
authors.forename: Marta
authors.initials: M
authors.lastname: Bombardo
authors.affiliation: Swiss Hepato-pancreato-biliary Centre, Department of Visceral and Transplantation Surgery, University Hospital, Zurich, Switzerland.
authors.forename: Raphael
authors.initials: R
authors.lastname: Buzzi
authors.affiliation: Swiss Hepato-pancreato-biliary Centre, Department of Visceral and Transplantation Surgery, University Hospital, Zurich, Switzerland.
authors.forename: Alberto B
authors.initials: AB
authors.lastname: Silva
authors.affiliation: Swiss Hepato-pancreato-biliary Centre, Department of Visceral and Transplantation Surgery, University Hospital, Zurich, Switzerland.
authors.forename: Ermanno
authors.initials: E
authors.lastname: Malagola
authors.affiliation: Swiss Hepato-pancreato-biliary Centre, Department of Visceral and Transplantation Surgery, University Hospital, Zurich, Switzerland.
authors.forename: Yinghua
authors.initials: Y
authors.lastname: Tian
authors.affiliation: Institute of Parasitology, University of Zurich, Switzerland.
authors.forename: Adrian B
authors.initials: AB
authors.lastname: Hehl
authors.affiliation: Institutes of Veterinary Anatomy and Virology, University of Zurich, Switzerland.
authors.forename: Elisabeth M
authors.initials: EM
authors.lastname: Schraner
authors.affiliation: Swiss Hepato-pancreato-biliary Centre, Department of Visceral and Transplantation Surgery, University Hospital, Zurich, Switzerland.
authors.forename: Gitta M
authors.initials: GM
authors.lastname: Seleznik
authors.affiliation: Swiss Hepato-pancreato-biliary Centre, Department of Visceral and Transplantation Surgery, University Hospital, Zurich, Switzerland.
authors.forename: Anja
authors.initials: A
authors.lastname: Zabel
authors.affiliation: Swiss Hepato-pancreato-biliary Centre, Department of Visceral and Transplantation Surgery, University Hospital, Zurich, Switzerland.
authors.forename: Theresia
authors.initials: T
authors.lastname: Reding
authors.affiliation: Swiss Hepato-pancreato-biliary Centre, Department of Visceral and Transplantation Surgery, University Hospital, Zurich, Switzerland.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Sonda
authors.affiliation: Swiss Hepato-pancreato-biliary Centre, Department of Visceral and Transplantation Surgery, University Hospital, Zurich, Switzerland.
authors.forename: Rolf
authors.initials: R
authors.lastname: Graf
mesh_terms: D061354:Acinar Cells / Q000166:cytology*; D000375:Aging; D000818:Animals; D054337:Cell Dedifferentiation / Q000502:physiology*; D004195:Disease Models, Animal; D015151:Immunoblotting; D007150:Immunohistochemistry; D008679:Metaplasia; D051379:Mice; D008810:Mice, Inbred C57BL; D046529:Microscopy, Electron, Transmission; D046790:Pancreas, Exocrine / Q000502:physiology*; D010195:Pancreatitis / Q000473:pathology; D012038:Regeneration; D012701:Serotonin / Q000378:metabolism*
chemical_list: D012701:Serotonin
keywords: ADM; acinar secretion; dedifferentiation; pancreatitis; partial pancreatectomy; regeneration; serotonin