Toxin-based selection of insulin-producing cells with improved defense properties for islet cell transplantation

Insulin-producing pancreatic beta-cells are known to be extremely susceptible to destruction, primarily by autoimmune mechanisms, infectious agents, and by chemical toxins that cause overt type I diabetes. As development of highly protected insulin-producing cells would be important for successful cell therapy of diabetic patients, gene transfection technique was utilized by several investigators in order to improve the defense properties of transplanted cells. In this article, we summarize other approaches based on a selection strategy that has been developed in our laboratory and by other research groups that engineer pancreatic beta-cells to provide protection against diabetogenic toxins (streptozotocin and alloxan), oxidative stress and cytokines. Selection strategies based on acute repeated or long-term continuous treatment of cell lines with cytotoxic agents have resulted in the selection of highly resistant cell subpopulations. We discuss possible involvement of different expression of cytoprotective genes in the selection of cell subpopulations, which demonstrate a broad spectrum of resistance. Importantly, toxin-based selection did not impair functional activity of the cells as it was shown in vitro. In addition, selected cells preserved their improved metabolic characteristics following encapsulation in alginate and subsequent implantation in diabetic animals. Identifying the mechanisms through which cell defense properties act will help clarify the process responsible for beta-cell regeneration in type I diabetes patients. Such knowledge might be useful in developing strategies focusing on the regeneration of beta-cell resistant populations.