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Differentiation of Affinity-Purified Human Pancreatic Duct Cells to ß-Cells

From the Section on Islet Transplantation and Cell Biology, Joslin Diabetes Center, Boston, Massachusetts

Address correspondence and reprint requests to Susan Bonner-Weir, PhD, Section on Islet Transplantation and Cell Biology, Joslin Diabetes Center, One Joslin Place, Boston, MA 02215. E-mail: susan.bonner-weir{at}joslin.harvard.edu

Abbreviations: EMT, epithelial-mesenchymal transition; HSP, heat shock protein; NCAM, neural cell adhesion molecule

To test whether pancreatic duct cells are in vitro progenitors, they were purified from dispersed islet-depleted human pancreatic tissue using CA19-9 antibody. The purified fraction was almost entirely CK19⁺ with no insulin⁺ cells, whereas the unpurified cells (crude duct) were 56% CK19⁺ and 0.4% insulin⁺ of total cells (0.7% of CK19⁺ cells). These cells were expanded as monolayers, aggregated under serum-free conditions, and transplanted into normoglycemic NOD/SCID mice. In crude duct grafts, insulin⁺ cells increased to 6.1% of CK19⁺ cells. Purified duct cells had slow expansion and poor aggregation, as well as engraftment. The addition of 0.1% cultured stromal cells improved these parameters. These stromal cells contained no CK19⁺ cells and no insulin by either quantitative RT-PCR or immunohistochemistry; stromal cell aggregates and grafts contained no insulin⁺ cells. Aggregation of purified duct plus stromal preparations induced insulin⁺ cells (0.1% of CK19⁺ cells), with further increase to 1.1% in grafts. Insulin mRNA mirrored these changes. In these grafts, all insulin⁺ cells were in duct-like structures, while in crude duct grafts, 85% were. Some insulin⁺ cells coexpressed duct markers (CK19 and CA19-9) and heat shock protein (HSP)27, a marker of nonislet cells, suggesting the transition from duct. Thus, purified duct cells from adult human pancreas can differentiate to insulin-producing cells.

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