English: A. “Pulse-chase” lineage-tracing studies (Dor et al. 2004; Nir et al. 2007) involve Cre-loxP-induced marking of pre-existing β-cells with heritable expression of a neutral transgene such as alkaline phosphatase (purple nuclei within blue β-cells, left). During homeostasis and growth, or following removal of β-cells by partial pancreatectomy or ablation with diphtheria toxin, β-cell numbers are maintained or restored by division of pre-existing β-cells (similar fraction of labeled β-cells after growth/injury, right). B. While there is no evidence for neogenesis from ductal cells in the uninjured pancreas (question mark, left), new Neurog3-expressing islet precursors appear after duct ligation, giving rise to new islet cells including β-cells (right) (Xu et al. 2008). Although Neurog3+ cells seem to derive from ducts, formal lineage-tracing has not ruled out the possibility that they might arise from centroacinar or acinar cells (question mark, right). This study predicts that pulse-chase labeling of pre-existing β-cells, before duct ligation, should reveal no contribution to the duct-derived β-cells that arise from injury-induced neogenesis (unlabeled islet cell nuclei).