How tissues generate and maintain the correct number of cells is a fundamental problem in biology. In principle, tissue turnover can occur by the differentiation of stem cells, as is well documentad for blood, skin and intestine, or by the duplication of existing differentiated cells. Recent work on adult stem cells has highlighted their potential contribution to organ maintenance and repair. However, the extent to which stem cells actually participate in these processes in vivo is not clear. Here we introduce a method for genetic lineage tracing to determine the contribution of stem cells to a tissue of interest. We focus on pancreatic β-cells, whose postnatal origins remain controversial. Our analysis shows that pro-existing β-cells, rather than pluripotent stem cells, are the major source of new β-cells during adult life and after pancreatectomy in mice. These results suggest that terminally differentiated β-cells retain a significant proliferative capacity in vivo and cast doubt on the idea that adult stem cells have a significant role in β-cell replenishment.
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Acknowledgements We thank J. Dubauskaite for zygote injection, G. Kenty for help with fluorescence-activated cell sorting analysis, H. Hsieh for technical assistance, and S. Bonner-Weir, A. Regev and members of the Melton laboratory for discussions. D.A.M. is a Howard Hughes Medical Institute Investigator. Y.D. was supported by EMBO and JDRF postdoctoral fellowships.