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Chronological Analysis With Fluorescent Timer Reveals Unique Features of Newly Generated β-Cells

机译:荧光计时器的时序分析揭示了新生成的β细胞的独特功能

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摘要

Although numerous studies have uncovered the molecular mechanisms regulating pancreas development, it remains to be clarified how β-cells arise from progenitors and how recently specified β-cells are different from preexisting β-cells. To address these questions, we developed a mouse model in which the insulin 1 promoter drives DsRed-E5 Timer fluorescence that shifts its spectrum over time. In transgenic embryos, green fluorescent β-cells were readily detected by FACS and could be distinguished from mature β-cells only until postnatal day 0, suggesting that β-cell neogenesis occurs exclusively during embryogenesis. Transcriptome analysis with green fluorescent cells sorted by FACS demonstrated that newly differentiated β-cells highly expressed progenitor markers, such as Sox9, Neurog3, and Pax4, showing the progenitor-like features of newborn β-cells. Flow cytometric analysis of cell cycle dynamics showed that green fluorescent cells were mostly quiescent, and differentiated β-cells were mitotically active. Thus, the precise temporal resolution of this model enables us to dissect the unique features of newly specified insulin-producing cells, which could enhance our understanding of β-cell neogenesis for future cell therapy.
机译:尽管许多研究已经揭示了调节胰腺发育的分子机制,但仍有待澄清β细胞是如何从祖细胞中产生的,以及最近指定的β细胞与已有的β细胞有何不同。为了解决这些问题,我们开发了一种小鼠模型,其中胰岛素1启动子驱动DsRed-E5 Timer荧光,其荧光随时间变化。在转基因胚胎中,FACS易于检测到绿色荧光β细胞,仅在出生后第0天才可以将其与成熟的β细胞区分开,这表明β细胞新生仅发生在胚胎发生过程中。用FACS分类的绿色荧光细胞进行的转录组分析表明,新分化的β细胞高度表达祖细胞标志物,例如Sox9,Neurog3和Pax4,显示了新生β细胞的祖细胞样特征。流式细胞仪分析细胞周期动力学结果表明,绿色荧光细胞大部分处于静止状态,而分化的β细胞具有有丝分裂活性。因此,该模型的精确时间分辨率使我们能够剖析新指定的产生胰岛素的细胞的独特特征,从而可以增强我们对β细胞新生的认识,以便将来进行细胞治疗。

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