A single-cell transcriptomic atlas of primate pancreatic islet aging.
A single-cell transcriptomic atlas of primate pancreatic islet aging.
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灵长类胰岛衰老的单细胞转录组图谱
DOI：
10.1093/nsr/nwaa127
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发表时间：
2021-03
影响因子：
20.6
通讯作者：
Qu J
中科院分区：
文献类型：
--
作者：
Li J;Zheng Y;Yan P;Song M;Wang S;Sun L;Liu Z;Ma S;Izpisua Belmonte JC;Chan P;Zhou Q;Zhang W;Liu GH;Tang F;Qu J
摘要随着年龄的增长，胰岛细胞的变性与糖耐量受损和糖尿病有关。内分泌细胞的衰老是异质性的，使揭开内分泌衰老背后的分子驱动因素的努力复杂化。为了克服这些障碍，我们对来自年轻和老年非糖尿病食蟹猴的胰岛细胞进行了单细胞RNA测序。尽管性别差异和转录变异增加，但随着蛋白质聚集体的积累，衰老的β细胞显示出更高的未折叠蛋白反应(UPR)。我们观察到与典型的ATF6和IRE1信号通路相关的UPR组分转录转录失调，包括在胰腺老化过程中的适应性UPR。值得注意的是，我们发现与衰老相关的β细胞特异性上调HSP90B1，一种位于内质网的伴侣蛋白，阻碍了高糖诱导的胰岛素分泌。我们的工作解码了在单细胞分辨率下导致胰岛功能衰退的与衰老相关的转录变化，并表明靶向UPR组分可能防止蛋白平衡的丧失，这暗示了一种延缓β细胞衰老和预防衰老相关糖尿病的途径。
Abstract Aging-related degeneration of pancreatic islet cells contributes to impaired glucose tolerance and diabetes. Endocrine cells age heterogeneously, complicating the efforts to unravel the molecular drivers underlying endocrine aging. To overcome these obstacles, we undertook single-cell RNA sequencing of pancreatic islet cells obtained from young and aged non-diabetic cynomolgus monkeys. Despite sex differences and increased transcriptional variations, aged β-cells showed increased unfolded protein response (UPR) along with the accumulation of protein aggregates. We observed transcriptomic dysregulation of UPR components linked to canonical ATF6 and IRE1 signaling pathways, comprising adaptive UPR during pancreatic aging. Notably, we found aging-related β-cell-specific upregulation of HSP90B1, an endoplasmic reticulum-located chaperone, impeded high glucose-induced insulin secretion. Our work decodes aging-associated transcriptomic changes that underlie pancreatic islet functional decay at single-cell resolution and indicates that targeting UPR components may prevent loss of proteostasis, suggesting an avenue to delaying β-cell aging and preventing aging-related diabetes.
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影响因子：
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通讯作者：
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