Pancreatic Islet-Autonomous Signals Modulate Identity Changes of Glucagon+ a-Cells

The mechanisms restricting regeneration and maintaining cell identity upon injury are poorly characterized in higher vertebrates. Upon ß-cell loss, 1-2% of the glucagon-producing a-cells spontaneously engage insulin production in mice. Here we explore the mechanisms of this plasticity. We show that the adaptive a-cell identity changes are constrained by intra-islet Insulin- and Smoothened-mediated signaling, among others. Combining ß-cell loss, or insulin signaling inhibition, with Smoothened inactivation in a- or d-cells, stimulates insulin production in more a-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 curbing an intrinsic trend of differentiated cells to change. Overall design: RNA-Seq analyses on five purified cells namely, mature a-cells, mature ß-cells, a-cells 30 days after DT, a-cells ectopically expressing PDX1 and a-cells expressing PDX1