Cano David A, Rulifson Ingrid C, Heiser Patrick W, Swigart Lamorna B, Pelengaris Stella, German Mike, Evan Gerard I, Bluestone Jeffrey A, Hebrok Matthias
Diabetes Center, University of California San Francisco, California, USA.
Diabetes. 2008 Apr;57(4):958-66. doi: 10.2337/db07-0913. Epub 2007 Dec 14.
Several studies have shown that the adult pancreas possesses a limited potential for beta-cell regeneration upon tissue injury. One of the difficulties in studying beta-cell regeneration has been the lack of a robust, synchronized animal model system that would allow controlled regulation of beta-cell loss and subsequent proliferation in adult pancreas. Here we present a transgenic mouse regeneration model in which the c-Myc transcription factor/mutant estrogen receptor (cMycER(TAM)) fusion protein can be specifically activated in mature beta-cells. We have studied these transgenic mice by immunohistochemical and biochemical methods to assess the ablation and posterior regeneration of beta-cells. Activation of the cMycER(TAM) fusion protein results in synchronous and selective beta-cell apoptosis followed by the onset of acute diabetes. Inactivation of c-Myc leads to gradual regeneration of insulin-expressing cells and reversal of diabetes. Our results demonstrate that the mature pancreas has the ability to fully recover from almost complete ablation of all existing beta-cells. Our results also suggest the regeneration of beta-cells is mediated by replication of beta-cells rather than neogenesis from pancreatic ducts.
多项研究表明，成年胰腺在组织损伤后β细胞再生的潜力有限。研究β细胞再生的困难之一在于缺乏一个强大的、同步的动物模型系统，该系统能够对成年胰腺中β细胞的损失及随后的增殖进行可控调节。在此，我们展示了一种转基因小鼠再生模型，其中c-Myc转录因子/突变雌激素受体（cMycER(TAM)）融合蛋白可在成熟β细胞中被特异性激活。我们通过免疫组织化学和生化方法研究了这些转基因小鼠，以评估β细胞的消融和后续再生情况。cMycER(TAM)融合蛋白的激活会导致同步且选择性的β细胞凋亡，随后引发急性糖尿病。c-Myc的失活会导致胰岛素表达细胞逐渐再生，糖尿病症状逆转。我们的结果表明，成熟胰腺有能力从几乎所有现有β细胞的完全消融中完全恢复。我们的结果还表明，β细胞的再生是由β细胞的复制介导的，而非来自胰腺导管的新生。
