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Serotonin promotes acinar dedifferentiation following pancreatitis-induced regeneration in the adult pancreas

Citation

Saponara, E and Grabliauskaite, K and Bombardo, M and Buzzi, R and Silva, AB and Malagola, E and Tian, Y and Hehl, AB and Schraner, EM and Seleznik, GM and Zabel, A and Reding, T and Sonda, S and Graf, R, Serotonin promotes acinar dedifferentiation following pancreatitis-induced regeneration in the adult pancreas, Journal of Pathology, 237, (4) pp. 495-507. ISSN 0022-3417 (2015) [Refereed Article]

Copyright Statement

Copyright 2015 Pathological Society of Great Britain and Ireland.

DOI: doi:10.1002/path.4595

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.

Item Details

Item Type:Refereed Article
Keywords:pancreatitis, serotonin, metaplasia, acinar secretion, dedifferentiation, regeneration, ADM, partial pancreatectomy
Research Division:Biological Sciences
Research Group:Biochemistry and Cell Biology
Research Field:Signal Transduction
Objective Division:Health
Objective Group:Clinical Health (Organs, Diseases and Abnormal Conditions)
Objective Field:Digestive System Disorders
ID Code:127551
Year Published:2015
Web of Science® Times Cited:10
Deposited By:Health Sciences
Deposited On:2018-08-02
Last Modified:2019-04-15
Downloads:0

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