1. ¹Department of Surgery, McGill University, Montréal, QC, Canada
2. ²Centre for Pancreatic Diseases, McGill University Health Centre, Montréal, QC, Canada
3. ³Biotechnology Research Institute, Montréal, QC, Canada
4. ⁴Department of Microbiology and Immunology, University of Montréal, Montréal, QC, Canada
5. ⁵INRS-IAF, University of Québec, Laval, QC, Canada

Correspondence: Dr L Rosenberg, MD, PhD, Montreal General Hospital C9-128, 1650 Cedar avenue, Montréal, QC, Canada H3G 1A4. E-mail: lawrence.rosenberg@mcgill.ca

Abstract

Cultured human islets can be dedifferentiated to duct-like structures composed mainly of cytokeratin⁺ and nestin⁺ cells. Given that these structures possess the potential to redifferentiate into islet-like structures, we sought to elucidate their specific cellular origins. Adenoviral vectors were engineered for -, -, - or PP-cell-specific GFP expression. A double-stranded system was designed whereby cultures were infected with two vectors: one expressed GFP behind the cumate-inducible promoter sequence, and the other expressed the requisite transactivator behind the human insulin, glucagon, somatostatin or pancreatic polypeptide promoter. This system labels hormone⁺ cells in the islet in a cell-specific manner, allowing these cells to be tracked during the course of transformation from islet to duct-like structure. Post-infection, islets were cultured to induce dedifferentiation. Fluorescence microscopy demonstrated that -, - and PP-cells contributed equally to the cytokeratin⁺ population, with minimal -cell contribution, whereas the converse was true for nestin⁺ cells. Complementary targeted cell ablation studies, using streptozotocin or similar adenoviral expression of the Bax (Bcl2-associated X protein) toxigene, validated these findings and suggested a redundancy between -, - and PP-cells with respect to cytokeratin⁺ cell derivation. These results call into question the traditional understanding of islet cells as being terminally differentiated and provide support for the concept of adult islet morphogenetic plasticity.