Pancreatic α-cell differentiation by mesenchyme-to-epithelial transition: implications for cell-based therapies in children

PurposeStem cell–derived tissue may provide a curative treatment for children with type 1 diabetes. Using an avian model, we have previously shown that foregut mesenchyme is able to differentiate into insulin-positive β-cell islets (B islets). Successful clinical islet transplantation, however, is reliant on graft tissue containing both insulin- and glucagon-secreting cells. Therefore, in this study, we assessed the ability of foregut mesenchyme to differentiate into glucagon-positive α-cell islets (A islets).MethodsChimeric recombinants (n = 14) were constructed using chick pancreatic epithelium combined with quail stomach mesenchyme from day 4 avian embryos and then cultured in 3 dimensions for 7 days. Cryosectioned recombinants were analyzed using immunocytochemistry against glucagon, insulin, and the quail-specific nucleolar antigen. The A islets and B islets were determined to be of solely epithelial, solely mesenchymal, or mixed origin according to the coexpression of the quail-specific nucleolar antigen.ResultsForty-eight A islets and 34 B islets were analyzed. Eighty-five percent of the A islets were solely derived from the epithelium, but, notably, 5% were solely derived from the mesenchyme and 10% were of mixed origin. A-islet differentiation from foregut mesenchyme was reduced as compared with B islets (P = .03).ConclusionWe demonstrate that foregut mesenchyme is able to differentiate into both α and β cells, albeit with quantitative differences. These findings may have important implications for the derivation of islet tissue from mesenchymal stem cells to cure juvenile-onset diabetes.