Evidence of a developmental origin of beta-cell heterogeneity using a dual lineage tracing technology

The Cre/loxP system has been used extensively in mouse models with a limitation of one lineage at a time. Differences in function and other properties among populations of adult beta-cells is termed beta-cell heterogeneity, which was recently associated with diabetic phenotypes. Nevertheless, the presence of a developmentally-derived beta-cell heterogeneity is unclear. Here, we developed a novel dual lineage tracing technology, using a combination of two recombinase systems, Dre/RoxP and Cre/LoxP, to independently trace green fluorescent Pdx1-lineage cells and red fluorescent Ptf1a-lineage cells in the developing and adult mouse pancreas. We detected a few Pdx1+/Ptf1a- lineage cells in addition to the vast majority of Pdx1+/Ptf1a+ lineage cells in the pancreas. Moreover, Pdx1+/Ptf1a+ lineage beta-cells had fewer Ki-67+ proliferating beta-cells, and expressed higher mRNA levels of insulin, Glut2, Pdx1, MafA and Nkx6.1, but lower CCND1 and CDK4, compared to Pdx1+/Ptf1a- lineage beta-cells. Furthermore, more TSQ-high, SSC-high cells were detected in the Pdx1+Ptf1a+ lineage population than in the Pdx1+Ptf1a- lineage population. Together, these data suggest that differential activation of Ptf1a in the developing pancreas may correlate with this beta-cell heterogeneity.