Conversion of adult pancreatic α-cells to β-cells after extreme β-cell loss

Pancreatic insulin-producing β-cells have a long lifespan, such that in healthy conditions they replicate little during a lifetime. Nevertheless, they show increased self-duplication after increased metabolic demand or after injury (that is, β-cell loss). It is not known whether adult mammals can differentiate (regenerate) new β-cells after extreme, total β-cell loss, as in diabetes. This would indicate differentiation from precursors or another heterologous (non-β-cell) source. Here we show β-cell regeneration in a transgenic model of diphtheria-toxin-induced acute selective near-total β-cell ablation. If given insulin, the mice survived and showed β-cell mass augmentation with time. Lineage-tracing to label the glucagon-producing α-cells before β-cell ablation tracked large fractions of regenerated β-cells as deriving from α-cells, revealing a previously disregarded degree of pancreatic cell plasticity. Such inter-endocrine spontaneous adult cell conversion could be harnessed towards methods of producing β-cells for diabetes therapies, either in differentiation settings in vitro or in induced regeneration. The insulin-producing β-cells of the pancreas are long lived and replicate little during a lifetime, but can duplicate upon injury or metabolic demand. Work in a transgenic mouse model in which β-cells are nearly almost completely ablated shows that adult α-cells, normally responsible for producing the peptide hormone glucagon, can be spontaneously reprogrammed to become β-cells. This unexpected display of pancreatic cell plasticity suggests possible diabetes therapies involving either differentiation settings for in vitro cell production or induced regeneration in vivo. And the production of new models for selective and total cell killing could reveal previously unrecognized cell plasticity in other organs. In the pancreas, insulin-producing β-cells are long-lived and generally replicate seldom. They can do so, however, after increased metabolic demand or after injury. Here, a new transgenic model is developed in which β-cells are nearly completely ablated in mice. If given insulin, these mice survive, and grow new β-cells. Lineage-tracing shows that these new β-cells come from α-cells, revealing a previously disregarded degree of pancreatic cell plasticity.