Diabetes Research Center, Vrije Universiteit Brussel, Brussels, Belgium.
Cell Death Dis. 2013 Mar 7;4(3):e523. doi: 10.1038/cddis.2013.52.
We previously showed that injury by partial duct ligation (PDL) in adult mouse pancreas activates Neurogenin 3 (Ngn3)(+) progenitor cells that can differentiate to β cells ex vivo. Here we evaluate the role of Ngn3(+) cells in β cell expansion in situ. PDL not only induced doubling of the β cell volume but also increased the total number of islets. β cells proliferated without extended delay (the so-called 'refractory' period), their proliferation potential was highest in small islets, and 86% of the β cell expansion was attributable to proliferation of pre-existing β cells. At sufficiently high Ngn3 expression level, upto 14% of all β cells and 40% of small islet β cells derived from non-β cells. Moreover, β cell proliferation was blunted by a selective ablation of Ngn3(+) cells but not by conditional knockout of Ngn3 in pre-existing β cells supporting a key role for Ngn3(+) insulin(-) cells in β cell proliferation and expansion. We conclude that Ngn3(+) cell-dependent proliferation of pre-existing and newly-formed β cells as well as reprogramming of non-β cells contribute to in vivo β cell expansion in the injured pancreas of adult mice.
我们之前的研究表明，成年小鼠胰腺的部分导管结扎（PDL）损伤会激活神经基因 3（Ngn3）（+）祖细胞，这些祖细胞可以在体外分化为β细胞。在这里，我们评估了 Ngn3（+）细胞在体内β细胞扩增中的作用。PDL 不仅诱导β细胞体积增加一倍，还增加了胰岛的总数。β细胞增殖没有延长的延迟（所谓的“不应期”），其增殖潜力在小胰岛中最高，并且 86%的β细胞扩增归因于现有β细胞的增殖。在足够高的 Ngn3 表达水平下，高达 14%的所有β细胞和 40%的小胰岛β细胞来源于非β细胞。此外，β细胞增殖受到 Ngn3（+）细胞选择性消融的抑制，但不受到条件性敲除现有β细胞中 Ngn3 的抑制，这支持 Ngn3（+）胰岛素（-）细胞在β细胞增殖和扩增中的关键作用。我们得出结论，Ngn3（+）细胞依赖性的现有和新形成的β细胞的增殖以及非β细胞的重编程有助于成年小鼠损伤胰腺中的体内β细胞扩增。
