Single-cell transcriptomes identify human islet cell signatures and reveal cell-type-specific expression changes in type 2 diabetes.
Single-cell transcriptomes identify human islet cell signatures and reveal cell-type-specific expression changes in type 2 diabetes.
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DOI：
10.1101/gr.212720.116
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发表时间：
2017-02
期刊：
影响因子：
7
通讯作者：
Stitzel ML
中科院分区：
文献类型：
--
作者：
Lawlor N;George J;Bolisetty M;Kursawe R;Sun L;Sivakamasundari V;Kycia I;Robson P;Stitzel ML
血糖水平受到至少四种构成胰岛的细胞类型的协调作用的严格控制。这些细胞的比例和/或功能的变化与单基因、1型和2型（T2 D）糖尿病的遗传和分子病理生理学相关。细胞异质性阻碍了对控制胰岛（dys）功能的每种胰岛细胞类型的分子组分的精确理解，特别是丰度较低的δ和γ/胰腺多肽（PP）细胞。在这里，我们报告了来自非糖尿病（ND）和T2 D人类胰岛样本的638个细胞的单细胞转录组。ND单细胞转录组的分析鉴定了不同的α、β、δ和PP/γ细胞类型特征。与罕见和常见形式的胰岛功能障碍和糖尿病相关的基因在δ和PP/γ细胞类型中表达。此外，这项研究表明，δ细胞特异性表达受体，这些受体接收和协调来自瘦素、生长激素释放肽和多巴胺信号传导途径的全身性信号，这暗示它们是胰岛中中枢和外周代谢信号的整合者。最后，单细胞转录组分析揭示了T2 D和ND α、β和δ细胞之间差异调节的基因，这些基因在配对的整个胰岛分析中检测不到。因此，这项研究确定了胰岛（dys）功能的基本细胞类型特异性特征，并为全面了解胰岛生物学和糖尿病发病机制提供了重要资源。
Blood glucose levels are tightly controlled by the coordinated action of at least four cell types constituting pancreatic islets. Changes in the proportion and/or function of these cells are associated with genetic and molecular pathophysiology of monogenic, type 1, and type 2 (T2D) diabetes. Cellular heterogeneity impedes precise understanding of the molecular components of each islet cell type that govern islet (dys)function, particularly the less abundant delta and gamma/pancreatic polypeptide (PP) cells. Here, we report single-cell transcriptomes for 638 cells from nondiabetic (ND) and T2D human islet samples. Analyses of ND single-cell transcriptomes identified distinct alpha, beta, delta, and PP/gamma cell-type signatures. Genes linked to rare and common forms of islet dysfunction and diabetes were expressed in the delta and PP/gamma cell types. Moreover, this study revealed that delta cells specifically express receptors that receive and coordinate systemic cues from the leptin, ghrelin, and dopamine signaling pathways implicating them as integrators of central and peripheral metabolic signals into the pancreatic islet. Finally, single-cell transcriptome profiling revealed genes differentially regulated between T2D and ND alpha, beta, and delta cells that were undetectable in paired whole islet analyses. This study thus identifies fundamental cell-type–specific features of pancreatic islet (dys)function and provides a critical resource for comprehensive understanding of islet biology and diabetes pathogenesis.