Pax4-Ghrelin mediates the conversion of pancreatic ɛ-cells to β-cells after extreme β-cell loss in zebrafish.

Pancreatic ɛ-cells producing ghrelin are one type of endocrine cell found in islets, which have been shown to influence other intra-islet cells, especially in regulating the function of β cells. However, the role of such cells during β-cell regeneration is heretofore unknown. Here, using a zebrafish nitroreductase (NTR)-mediated β-cells ablation model, we uncover that ghrelin-positive ɛ-cells in the pancreas act as contributors to neogenic β-cells after extreme β-cell loss. Further studies show the overexpression of ghrelin or the expansion of ɛ-cells potentiates β-cell regeneration. Lineage tracing confirms a proportion of embryonic ɛ-cells can transdifferentiate to β-cells, and the deletion of Pax4 enhances this transdifferentiation of ɛ-cells to β-cells. Mechanistically, Pax4 binds to the ghrelin regulatory region and represses its transcription. Thus deletion of Pax4 derepresses ghrelin expression and causes producing more ghrelin-positive cells, enhancing the transdifferentiation of ɛ-cells to β-cells and consequent potentiating β-cells regeneration. Our findings reveal a novel role of ɛ-cells during zebrafish β-cell regeneration, indicating Pax4 regulates ghrelin transcription and mediates the conversion of embryonic ɛ-cells to β-cells after extreme β-cell loss.