Can beta-cells be derived from exocrine pancreas?
A major goal of research aiming at improving islet cell replacement therapy is to find the most suitable progenitor cell type from which functional beta-cells can be generated in large numbers. Many possibilities have been raised, including beta-cells themselves, embryonic or adult stem cells and reprogramming of other cell types. Some of these progenitor types may be active or reside in a dormant state in adults in vivo, while others can be rather considered to be products of tissue engineering in vitro. Starting from the available pancreas organs from cadaveric donors, an attractive possibility is to reprogram acinar exocrine cells into beta-cells. Indeed, acinar cells isolated from adult rats display a pronounced plasticity in culture. After an initial step of dedifferentiation, they can be redirected to the beta-cell phenotype by adding agonists of the JAK2/STAT3 signalling pathway to the medium (epidermal growth factor and leukaemia inhibitory factor). The acinar cells that undergo exocrine-to-endocrine transdifferentiation first need to re-express neurogenin-3 and then need to escape inhibition by Notch signalling. The insulin-expressing cells that are generated in this way are glucose-regulated and can normalize glycaemia after transplantation into diabetic immunocompromised mice. It will now be important to translate these findings to human cells.