Reprogramming of non-beta islet cells

Abstract

Using methods of genetic (i.e., irreversible) cell labeling in mice to trace and delineate lineages of cells in the body, in combination with the selective ablation of specific cell types in vivo, we found that the adult pancreas has the ability to regenerate new functional insulin-producing cells through spontaneous cell identity changes occurring in islet non-β- cells. All islet non-β-cells have the potential to become insulin producers.

We have subsequently shown that human α- and γ-cells can also become glucose-sensitive insulin-producing cells. Our studies also stress the importance of the islet three-dimensional architecture to harness islet cell plasticity.

This plasticity could be exploited to reprogram non-β-cells into β-like cells to treat diabetes. Would it be possible to therapeutically promote the islet cell conversion in patients? One additional advantage of promoting insulin production by non-β-cells is that it would encompass a decreased glucagon production in autoimmune diabetes.

In the lab we are seeking to determine how to exploit this phenomenon of cellular reprogramming to propose an entirely new therapeutic strategy for diabetes. Interestingly, despite showing glucose-stimulated insulin secretion and leading to diabetes remission when transplanted into diabetic mice, converted human α-cells maintain an α-cell genetic signature and display a hybrid phenotype. This feature might be most valuable, because such a hybrid character could help evading the immune system when autoimmunity has developed.

Biology textbooks teach us that mature and fully differentiated adult cell types remain fixed in the identity they have acquired upon maturation and differentiation. By inducing non- insulin-producing human pancreatic cells to modify their function to produce and secrete insulin in response to glucose, we show that the adaptive capacity of our cells is much greater than previously thought. Moreover, human cell plasticity would not be exclusive to the pancreas. Direct reprogramming appears to be a promising avenue to treat not only diabetes but also other degenerative diseases, namely, diseases resulting from massive and premature cell death.