Precursor cells in mouse islets generate new beta-cells in vivo during aging and after islet injury.

Whereas it is believed that the pancreatic duct contains endocrine precursors, the presence of insulin progenitor cells residing in islets remain controversial. We tested whether pancreatic islets of adult mice contain precursor beta-cells that initiate insulin synthesis during aging and after islet injury. We used bigenic mice in which the activation of an inducible form of Cre recombinase by a one-time pulse of tamoxifen results in the permanent expression of a floxed human placental alkaline phosphatase (PLAP) gene in 30% of pancreatic beta-cells. If islets contain PLAP(-) precursor cells that differentiate into beta-cells (PLAP(-)IN(+)), a decrease in the percentage of PLAP(+)IN(+) cells per total number of IN(+) cells would occur. Conversely, if islets contain PLAP(+)IN(-) precursors that initiate synthesis of insulin, the percentage of PLAP(+)IN(+) cells would increase. Confocal microscope analysis revealed that the percentage of PLAP(+)IN(+) cells in islets increased from 30 to 45% at 6 months and to 60% at 12 months. The augmentation in the level of PLAP in islets with time was confirmed by real-time PCR. Our studies also demonstrate that the percentage of PLAP(+)IN(+) cells in islets increased after islet injury and identified putative precursors in islets. We postulate that PLAP(+)IN(-) precursors differentiate into insulin-positive cells that participate in a slow renewal of the beta-cell mass during aging and replenish beta-cells eliminated by injury.