Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, Israel.
Department of Chemical Research Support, Weizmann Institute of Science, Rehovot 7610001, Israel.
Dev Cell. 2019 Jan 7;48(1):115-125.e4. doi: 10.1016/j.devcel.2018.11.001. Epub 2018 Nov 29.
Pancreatic beta cells have been shown to be heterogeneous at multiple levels. However, spatially interrogating transcriptional heterogeneity in the intact tissue has been challenging. Here, we developed an optimized protocol for single-molecule transcript imaging in the intact pancreas and used it to identify a sub-population of "extreme" beta cells with elevated mRNA levels of insulin and other secretory genes. Extreme beta cells contain higher ribosomal and proinsulin content but lower levels of insulin protein in fasted states, suggesting they may be tuned for basal insulin secretion. They exhibit a distinctive intra-cellular polarization pattern, with elevated mRNA concentrations in an apical ER-enriched compartment, distinct from the localization of nascent and mature proteins. The proportion of extreme cells increases in db/db diabetic mice, potentially facilitating the required increase in basal insulin. Our results thus highlight a sub-population of beta cells that may carry distinct functional roles along physiological and pathological timescales.
胰岛β细胞在多个层面上表现出异质性。然而，在完整组织中对转录异质性进行空间分析一直具有挑战性。在这里，我们开发了一种优化的用于完整胰腺中单分子转录本成像的方案，并利用该方案鉴定了一个具有升高的胰岛素和其他分泌基因 mRNA 水平的“极端”β细胞亚群。极端β细胞含有更高的核糖体和胰岛素原含量，但在空腹状态下胰岛素蛋白水平较低，这表明它们可能针对基础胰岛素分泌进行了调整。它们表现出独特的细胞内极化模式，在富含内质网的顶端隔室中 mRNA 浓度升高，与新生和成熟蛋白的定位不同。在 db/db 糖尿病小鼠中，极端细胞的比例增加，可能有助于基础胰岛素的必需增加。因此，我们的研究结果突出了β细胞的一个亚群，该亚群可能在生理和病理时间尺度上具有不同的功能作用。
