Paracrine Secretion of Transforming Growth Factor ß by Ductal Cells Promotes Acinar-to-Ductal Metaplasia in Cultured Human Exocrine Pancreas Tissues.

ABSTRACT

OBJECTIVE: We aimed to evaluate the contribution of acinar-to-ductal metaplasia (ADM) to the accumulation of cells with a ductal phenotype in cultured human exocrine pancreatic tissues and reveal the underlying mechanism. METHODS: We sorted and cultured viable cell populations in human exocrine pancreatic tissues with a flow cytometry-based lineage tracing method to evaluate possible mechanisms of ADM. Cell surface markers, gene expression pattern, and sphere formation assay were used to examine ADM. RESULTS: A large proportion of acinar cells gained CD133 expression during the 2-dimensional culture and showed down-regulation of acinar markers and up-regulation of ductal markers, assuming an ADM phenotype. In a serum-free culture condition, ADM induction was mainly dependent on transforming growth factor ß (TGF-ß) secreted from cultured ductal cells. Human acinar cells when cultured alone for a week in a serum-free condition do not undergo ADM. However, serum may contain other factors besides TGF-ß to induce ADM in human acinar cells. In addition, we found that TGF-ß cannot induce ADM of murine acinar cells. CONCLUSIONS: Ductal cells are the major source of TGF-ß that induces ADM in cultured human exocrine pancreatic tissues. This culture system might be a useful model to investigate the mechanism of ADM in human cells.