Cdk4 regulates recruitment of quiescent beta-cells and ductal epithelial progenitors to reconstitute beta-cell mass.
Cdk4 regulates recruitment of quiescent beta-cells and ductal epithelial progenitors to reconstitute beta-cell mass.
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DOI：
10.1371/journal.pone.0008653
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发表时间：
2010-01-13
期刊：
影响因子：
3.7
通讯作者：
Rane SG
中科院分区：
文献类型：
--
作者：
Lee JH;Jo J;Hardikar AA;Periwal V;Rane SG
在糖尿病中，产生胰岛素的胰岛 β 细胞（β 细胞）被破坏、严重耗竭或功能受损。因此，替代功能性β细胞群将促进临床糖尿病管理。我们之前已经证明了 Cdk4 在调节 β 细胞质量中的重要性。 Cdk4 缺陷小鼠表现出 β 细胞发育不全并发展为糖尿病，而在表达活性 Cdk4R24C 激酶的小鼠中观察到 β 细胞增生。虽然 β 细胞复制似乎是导致 β 细胞质量增加的主要机制，但大量证据也支持胰腺导管上皮在新 β 细胞生成中的贡献。此外，虽然人们认为大多数β细胞处于“休眠”状态，但尚不清楚是否以及在多大程度上可以诱导休眠细胞参与β细胞再生反应。在这里，我们使用 Cdk4 突变小鼠的部分胰腺切除术 (PX) 模型来解决这些问题。为了精确研究再生过程的动力学，我们进行了基于 DNA 类似物的谱系追踪研究，然后进行了数学建模。 PX 后一周内，我们观察到胰岛 β 细胞和导管上皮细胞大量增殖。有趣的是，数学模型表明，将静止细胞招募到活跃细胞周期中可以促进 Cdk4R24C 胰腺中 β 细胞群的重建。此外，在 PX 后 24-48 小时内，表达转录因子 Pdx-1 的导管上皮细胞急剧增加。我们还在导管上皮中检测到胰岛素阳性细胞，并且 Cdk4R24C 胰腺中的胰岛样细胞簇显着增加。我们得出结论，Cdk4不仅促进β细胞复制，而且促进导管上皮中β细胞祖细胞的激活。此外，我们还发现 Cdk4 通过招募静止细胞进入细胞周期来控制 β 细胞质量。比较细胞增殖和胰岛样簇对胰岛素阳性细胞总数增加的贡献，表明迄今为止未表征的巨大非增殖贡献。
Insulin-producing pancreatic islet β cells (β-cells) are destroyed, severely depleted or functionally impaired in diabetes. Therefore, replacing functional β-cell mass would advance clinical diabetes management. We have previously demonstrated the importance of Cdk4 in regulating β-cell mass. Cdk4-deficient mice display β-cell hypoplasia and develop diabetes, whereas β-cell hyperplasia is observed in mice expressing an active Cdk4R24C kinase. While β-cell replication appears to be the primary mechanism responsible for β-cell mass increase, considerable evidence also supports a contribution from the pancreatic ductal epithelium in generation of new β-cells. Further, while it is believed that majority of β-cells are in a state of ‘dormancy’, it is unclear if and to what extent the quiescent cells can be coaxed to participate in the β-cell regenerative response. Here, we address these queries using a model of partial pancreatectomy (PX) in Cdk4 mutant mice. To investigate the kinetics of the regeneration process precisely, we performed DNA analog-based lineage-tracing studies followed by mathematical modeling. Within a week after PX, we observed considerable proliferation of islet β-cells and ductal epithelial cells. Interestingly, the mathematical model showed that recruitment of quiescent cells into the active cell cycle promotes β-cell mass reconstitution in the Cdk4R24C pancreas. Moreover, within 24–48 hours post-PX, ductal epithelial cells expressing the transcription factor Pdx-1 dramatically increased. We also detected insulin-positive cells in the ductal epithelium along with a significant increase of islet-like cell clusters in the Cdk4R24C pancreas. We conclude that Cdk4 not only promotes β-cell replication, but also facilitates the activation of β-cell progenitors in the ductal epithelium. In addition, we show that Cdk4 controls β-cell mass by recruiting quiescent cells to enter the cell cycle. Comparing the contribution of cell proliferation and islet-like clusters to the total increase in insulin-positive cells suggests a hitherto uncharacterized large non-proliferative contribution.
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