In Vivo Lineage Tracing Defines the Role of Acinar-to-Ductal Transdifferentiation in Inflammatory Ductal Metaplasia

Background & Aims: Chronic injury results in regeneration of normal pancreatic tissue and formation of a metaplasia of ductal phenotype. Metaplastic ductal lesions are seen in pancreatitis as well as in specimens of pancreatic cancer and are thought to represent a condition with increased risk of neoplasia. Acinar-to-ductal transdifferentiation is thought to be the source of this metaplasia. This has been suggested for flat duct-like lesions called tubular complexes and for lesions exhibiting a mucinous metaplasia. However, available studies are based on interpretation of static data rather than on direct evidence. Transdifferentiation from acinar to ductal cells has never been confirmed in the adult pancreas. Methods: Here, we use Cre-loxP-based genetic lineage tracing in vivo to investigate whether transdifferentiation of acinar cells contributes to regeneration and metaplasia in pancreatitis. Results: The results show that transdifferentiation does not play a role in regeneration of normal tissue. Acinar cells are regenerated by preexisting acinar cells and not from other cell types. Three different types of metaplastic ductal lesions are observed and analyzed. Whereas the majority of metaplastic lesions are not of acinar origin, acinar-to-ductal transdifferentiation is identified in a minority of mucinous metaplastic lesions. Conclusions: Here, we provide direct evidence that acinar-to-ductal transdifferentiation occurs in the adult pancreas in vivo. However, it accounts for only a minority of metaplastic lesions.