Non-β-cell progenitors of β-cells in pregnant mice

Pregnancy is a normal physiological condition in which the maternal beta-cell mass increases rapidly about two-fold to adapt to new metabolic challenges. We have used a lineage tracing of beta-cells to analyse the origin of new beta-cells during this rapid expansion in pregnancy. Double transgenic mice bearing a tamoxifen-dependent Cre-recombinase construct under the control of a rat insulin promoter, together with a reporter Z/AP gene, were generated. Then, in response to a pulse of tamoxifen before pregnancy, beta-cells in these animals were marked irreversibly and heritably with the human placental alkaline phosphatase (HPAP). First, we conclude that the lineage tracing system was highly specific for beta-cells. Secondly, we scored the proportion of the beta-cells marked with HPAP during a subsequent chase period in pregnant and non-pregnant females. We observed a dilution in this labeling index in pregnant animal pancreata, compared to nonpregnant controls, during a single pregnancy in the chase period. To extend these observations we also analyzed the labeling index in pancreata of animals during the second of two pregnancies in the chase period. The combined data revealed statistically-significant dilution during pregnancy, indicating a contribution to new beta cells from a non-beta-cell source. Thus for the first time in a normal physiological condition, we have demonstrated not only beta-cell duplication, but also the activation of a non-beta-cell progenitor population. Further, there was no transdifferentiation of beta-cells to other cell types in a two and half month period following labeling, including the period of pregnancy.