Induced cell clustering enhances islet β cell formation from pancreatic ductal epithelial cells

Although islet transplantation holds great promise as a treatment for diabetes, a major limitation to its future clinical use is a shortage of donor tissue. During both fetal development and adult pancreatic regeneration, pancreatic ductal epithelial cells (PDEC) differentiate into endocrine cells. The goal of this project is to apply existing understanding of these processes to stimulate islet cell differentiation in vitro. Following 11-14 days of culturing adult human PDEC in a standard cell culture environment (tissue culture treated plastic, 10% FBS), they transdifferentiate to β cells at an extremely low efficiency (0.1%). β-cell differentiation was enhanced greater than 4-fold (0.42%) when PDEC were grown on a low adhesive substrate (nontreated plastic) and in a low serum medium (5% Nu serum), conditions which are permissive to cell detachment and clustering. While the overall efficiency of transdifferentiation was still very low, the results suggest that induced cell-cell interactions and cell shape changes may be critical to stimulating β-cell production in vitro. We are currently exploring additional factors (ECM factors, growth factors, transcription factors) that may improve the efficiency of transdifferentiation in order to optimize the creation of tissue-engineered islets.