Beta cell transdifferentiation does not contribute to preneoplastic/metaplastic ductal lesions of the pancreas by genetic lineage tracing in vivo.
Inflammatory injury to the pancreas results in regeneration of normal tissue and formation of metaplastic lesions of a ductal phenotype. These metaplastic ductal lesions (MDL) are called tubular complexes (TC), mucinous metaplasia, or pancreatic intraepithelial neoplasia. Because they are regularly found in chronic pancreatitis and pancreatic cancer, their formation is thought to represent a step in inflammation-mediated carcinogenesis. Despite these lesions' ductal character, their origin is controversial. All known pancreatic cell lineages have been suggested as the origin. In vitro studies suggest that differentiated cells in the pancreas remain highly plastic and can transdifferentiate as a mechanism of regeneration and metaplasia. In vivo studies suggest that islets, specifically beta cells, may be the cell of origin. However, in vitro studies are subject to ductal cell contamination, and previous in vivo studies interpret static data rather than direct evidence. Using genetic lineage tracing in vivo, we investigate whether transdifferentiation of beta cells contributes to regeneration or metaplasia in pancreatitis. RIP-CreER;Z/AP mice were used to heritably tag beta cells in the adult pancreas. Injury by cerulein pancreatitis resulted in regeneration of normal tissue and metaplasia with formation of two distinct types of TC and mucinous lesions. Lineage tracing revealed that none of these MDL are of beta cell origin; nor do beta cells contribute to regeneration of normal acinar and ductal tissue, which indicates that the plasticity of differentiated pancreatic islet cells, suggested by earlier static and in vitro studies, plays no role in regeneration, metaplasia, and carcinogenesis in vivo.
Strobel
Oliver
O
Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
Dor
Yuval
Y
Stirman
Amy
A
Trainor
Amanda
A
Fernández-del Castillo
Carlos
C
Warshaw
Andrew L
AL
Thayer
Sarah P
SP
D000818:Animals; D003585:Cell Biology; D002454:Cell Differentiation; D019070:Cell Lineage; D004847:Epithelial Cells / Q000166:cytology; D005838:Genotype; D007249:Inflammation; D050417:Insulin-Secreting Cells / Q000166:cytology*; D008679:Metaplasia / Q000473:pathology; D051379:Mice; D046790:Pancreas, Exocrine / Q000166:cytology / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D012038:Regeneration