Pancreatic Islet-Autonomous Insulin and Smoothened-Mediated Signaling Modulate Identity Changes of Glucagon(+) α-Cells

The mechanisms restricting regeneration and maintaining cell identity following injury are poorly characterized in higher vertebrates. Upon β-cell loss, 1–2% of the glucagon-producing α-cells spontaneously engage in insulin production in mice. Here we explore the mechanisms inhibiting α-cell plasticity. We show that the adaptive α-cell identity changes are constrained by intra-islet Insulin- and Smoothened-mediated signaling, among others. The combination of β-cell loss, or insulin signaling inhibition, with Smoothened inactivation in α- or δ-cells, stimulates insulin production in more α-cells. These findings suggest that removing constitutive “brake signals” is crucial for neutralizing the refractoriness to adaptive cell-fate changes. It appears that cell identity maintenance is an active process mediated by repressive signals, released by neighbor cells, curbing an intrinsic trend of differentiated cells to change.