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首页> 外文期刊>Cell cycle >Overexpression of E2F3 promotes proliferation of functional human β cells without induction of apoptosis
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Overexpression of E2F3 promotes proliferation of functional human β cells without induction of apoptosis

机译：E2F3的过表达促进功能性人β细胞的增殖而不诱导凋亡

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The mechanisms that control proliferation, or lack thereof, in adult human β cells are poorly understood. Controlled induction of proliferation could dramatically expand the clinical application of islet cell transplantation and represents an important component of regenerative approaches to a functional cure of diabetes. Adult human β cells are particularly resistant to common proliferative targets and often dedifferentiate during proliferation. Here we show that expression of the transcription factor E2F3 has a role in regulating β-cell quiescence and proliferation. We found human islets have virtually no expression of the pro-proliferative G1/S transcription factors E2F1-3, but an abundance of inhibitory E2Fs 4-6. In proliferative human insulinomas, inhibitory E2Fs were absent, while E2F3 is expressed. Using this pattern as a "roadmap" for proliferation, we demonstrated that ectopic expression of nuclear E2F3 induced significant expansion of insulin-positive cells in both rat and human islets. These cells did not undergo apoptosis and retained their glucoseresponsive insulin secretion, showing the ability to reverse diabetes in mice. Our results suggest that E2F4-6 may help maintain quiescence in human β cells and identify E2F3 as a novel target to induce proliferation of functional β cells. Refinement of this approach may increase the islets available for cell-based therapies and research and could provide important cues for understanding in vivo proliferation of β cells.
机译：对成年人类β细胞控制增殖或缺乏增殖的机制了解甚少。受控地诱导增殖可以显着扩大胰岛细胞移植的临床应用，并且代表了用于糖尿病的功能治愈的再生方法的重要组成部分。成年人β细胞对常见的增殖靶点特别有抵抗力，并且在增殖过程中通常会去分化。在这里，我们表明转录因子E2F3的表达在调节β细胞的静止和增殖中具有作用。我们发现人类胰岛实际上不表达促增殖G1 / S转录因子E2F1-3，但是大量抑制性E2Fs 4-6。在增生性人胰岛素瘤中，不存在抑制性E2F，而表达E2F3。使用这种模式作为增殖的“路线图”，我们证明了核E2F3的异位表达在大鼠和人类胰岛中均诱导了胰岛素阳性细胞的显着扩增。这些细胞未发生凋亡，并保留了其葡萄糖反应性胰岛素分泌，显示了逆转小鼠糖尿病的能力。我们的结果表明，E2F4-6可能有助于维持人β细胞的静止状态，并将E2F3鉴定为诱导功能性β细胞增殖的新靶标。改进此方法可能会增加可用于基于细胞的疗法和研究的胰岛，并且可能为理解β细胞的体内增殖提供重要线索。

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