Laboratory of Developmental Biology & Metabolism, Institute for Molecular and Cellular Regulation, Gunma University, Gunma, Japan.
Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
Diabetologia. 2021 Dec;64(12):2803-2816. doi: 10.1007/s00125-021-05560-x. Epub 2021 Sep 9.
AIMS/HYPOTHESIS: Pancreatic polypeptide (PP) cells, which secrete PP (encoded by the Ppy gene), are a minor population of pancreatic endocrine cells. Although it has been reported that the loss of beta cell identity might be associated with beta-to-PP cell-fate conversion, at present, little is known regarding the characteristics of Ppy-lineage cells.
We used Ppy-Cre driver mice and a PP-specific monoclonal antibody to investigate the association between Ppy-lineage cells and beta cells. The molecular profiles of endocrine cells were investigated by single-cell transcriptome analysis and the glucose responsiveness of beta cells was assessed by Ca imaging. Diabetic conditions were experimentally induced in mice by either streptozotocin or diphtheria toxin.
Ppy-lineage cells were found to contribute to the four major types of endocrine cells, including beta cells. Ppy-lineage beta cells are a minor subpopulation, accounting for 12-15% of total beta cells, and are mostly (81.2%) localised at the islet periphery. Unbiased single-cell analysis with a Ppy-lineage tracer demonstrated that beta cells are composed of seven clusters, which are categorised into two groups (i.e. Ppy-lineage and non-Ppy-lineage beta cells). These subpopulations of beta cells demonstrated distinct characteristics regarding their functionality and gene expression profiles. Ppy-lineage beta cells had a reduced glucose-stimulated Ca signalling response and were increased in number in experimental diabetes models.
CONCLUSIONS/INTERPRETATION: Our results indicate that an unexpected degree of beta cell heterogeneity is defined by Ppy gene activation, providing valuable insight into the homeostatic regulation of pancreatic islets and future therapeutic strategies against diabetes.
The single-cell RNA sequence (scRNA-seq) analysis datasets generated in this study have been deposited in the Gene Expression Omnibus (GEO) under the accession number GSE166164 ( www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE166164 ).
目的/假设：胰腺多肽（PP）细胞分泌 PP（由 Ppy 基因编码），是胰腺内分泌细胞的一个小群体。虽然已经报道说β细胞身份的丧失可能与β-PP 细胞命运转换有关，但目前对于 Ppy 谱系细胞的特征知之甚少。
我们使用 Ppy-Cre 驱动小鼠和一种 PP 特异性单克隆抗体来研究 Ppy 谱系细胞与β细胞之间的关系。通过单细胞转录组分析研究内分泌细胞的分子特征，并通过 Ca 成像评估β细胞的葡萄糖反应性。通过链脲佐菌素或白喉毒素实验性诱导小鼠发生糖尿病。
发现 Ppy 谱系细胞有助于包括β细胞在内的四种主要类型的内分泌细胞。Ppy 谱系β细胞是一个较小的亚群，占总β细胞的 12-15%，主要（81.2%）位于胰岛周边。使用 Ppy 谱系示踪剂进行无偏单细胞分析表明，β细胞由七个簇组成，分为两组（即 Ppy 谱系和非 Ppy 谱系β细胞）。这些β细胞亚群在功能和基因表达谱方面表现出不同的特征。Ppy 谱系β细胞的葡萄糖刺激 Ca 信号反应降低，在实验性糖尿病模型中数量增加。
结论/解释：我们的结果表明，β细胞的异质性程度出乎意料地由 Ppy 基因激活定义，为胰腺胰岛的稳态调节和未来的糖尿病治疗策略提供了有价值的见解。
本研究中生成的单细胞 RNA 序列（scRNA-seq）分析数据集已在基因表达综合数据库（GEO）中以注册号 GSE166164 （www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE166164）进行了存储。
