Pancreatic alpha-cell differentiation by mesenchyme-to-epithelial transition: implications for cell-based therapies...

Stem 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 beta-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 alpha-cell islets (A islets).

Chimeric 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.

Forty-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).

We demonstrate that foregut mesenchyme is able to differentiate into both alpha and beta 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.