Where do postnatal pancreatic β-cells come from? During pancreatic maintenance and repair, do they arise from the differentiation of adult stem cells or from the duplication of differentiated cells? This controversial question has lacked a definitive answer, but the former theory has prevailed. The results now reported in Nature by Melton and colleagues are therefore a surprise.

The authors designed a genetic-lineage-tracing method that allowed them to trace the roots of postnatal pancreatic β-cells — more specifically, to distinguish between stem-cell-derived β-cells and β-cells that are the progeny of pre-existing β-cells. This method involved generating a transgenic mouse strain, in which adult β-cells were labelled in a heritable way.

The transgenic mice contained a gene that was under the control of the insulin promoter, which ensured that it was only expressed in β-cells. This gene encoded a recombinase that was inactive in the absence of the synthetic hormone tamoxifen. However, after tamoxifen injection, the transiently activated recombinase could remove a transcriptional stop signal from a reporter gene, such that this reporter gene is then expressed in a constitutive and heritable way.

Administering a 'pulse' of tamoxifen to these transgenic mice therefore resulted in reporter-protein production in the insulin-expressing cells that were present at the time of injection, as well as in their progeny. So, after a 'chase' period, during which cell turnover occurs, β-cells could be examined for the presence of the reporter-protein label. β-cells that are made after the pulse would only be labelled if they are the progeny of pre-existing β-cells; new β-cells that were derived from any non-β-cell source would not be labelled.

Using this approach, Melton and co-workers showed that pre-existing β-cells, rather than adult stem cells, are the main source of new β-cells in mice, both during normal adult life and after a partial pancreatectomy. “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.” The latter point has implications for cell-based therapies for type-I diabetes, although it remains to be shown that human β-cells replicate like mouse β-cells. Furthermore, this study has provided a way to assess how stem cells contribute to other organs during growth, normal turnover and regeneration.