Neurogenin3 phosphorylation controls reprogramming efficiency of pancreatic ductal organoids into endocrine cells.
Neurogenin3 phosphorylation controls reprogramming efficiency of pancreatic ductal organoids into endocrine cells.
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DOI：
10.1038/s41598-018-33838-5
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发表时间：
2018-10-18
影响因子：
4.6
通讯作者：
Philpott A
中科院分区：
文献类型：
--
作者：
Azzarelli R;Rulands S;Nestorowa S;Davies J;Campinoti S;Gillotin S;Bonfanti P;Göttgens B;Huch M;Simons B;Philpott A
β细胞替代已被提议作为某些形式糖尿病的有效治疗方法，并且正在广泛探索体外产生β细胞的方法。 β 细胞的潜在来源来自外分泌胰腺细胞向内分泌谱系的命运转变，通过胰腺内分泌形成和 β 细胞身份的三种调节因子 Ngn3、Pdx1 和 MafA 的过度表达。最近开发出胰腺导管类器官培养物，可以无限扩展，同时保持分化为内分泌谱系的潜力。在这里，使用小鼠胰腺导管类器官，我们发现 Ngn3、Pdx1 和 MafA 的共表达是产生表达胰岛素并在转录组范围内类似于 β 细胞的细胞所必需的且足够的。通过防止 Ngn3 蛋白的磷酸化可以显着提高 β 样细胞生成的效率，并通过促进分化的条件进一步增强。总而言之，我们的新发现强调了导管类器官培养物作为生成 β 样细胞的来源材料的潜力，并证明重编程因子的翻译后调节可用于增强 β 细胞的生成。
β-cell replacement has been proposed as an effective treatment for some forms of diabetes, and in vitro methods for β-cell generation are being extensively explored. A potential source of β-cells comes from fate conversion of exocrine pancreatic cells into the endocrine lineage, by overexpression of three regulators of pancreatic endocrine formation and β-cell identity, Ngn3, Pdx1 and MafA. Pancreatic ductal organoid cultures have recently been developed that can be expanded indefinitely, while maintaining the potential to differentiate into the endocrine lineage. Here, using mouse pancreatic ductal organoids, we see that co-expression of Ngn3, Pdx1 and MafA are required and sufficient to generate cells that express insulin and resemble β-cells transcriptome-wide. Efficiency of β-like cell generation can be significantly enhanced by preventing phosphorylation of Ngn3 protein and further augmented by conditions promoting differentiation. Taken together, our new findings underline the potential of ductal organoid cultures as a source material for generation of β-like cells and demonstrate that post-translational regulation of reprogramming factors can be exploited to enhance β-cell generation.
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影响因子：
4
作者：
Bonfanti, Paola;Nobecourt, Estelle;Scharfmann, Raphael
通讯作者：
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影响因子：
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作者：
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通讯作者：
Philpott, Anna
影响因子：
7.7
作者：
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