Characterisation of Ppy-lineage cells clarifies the functional heterogeneity of pancreatic beta cells in mice,Diabetologia

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Characterisation of Ppy-lineage cells clarifies the functional heterogeneity of pancreatic beta cells in mice
Diabetologia ( IF 8.4 ) Pub Date : 2021-09-09 , DOI: 10.1007/s00125-021-05560-x
Takahiro Fukaishi _{1,

2} , Yuko Nakagawa ₁ , Ayako Fukunaka ₁ , Takashi Sato ₁ , Akemi Hara _{3,

4,

5} , Keiko Nakao ₅ , Michiko Saito _{6,

7} , Kenji Kohno ₆ , Takeshi Miyatsuka _{3,

4} , Motoyuki Tamaki ₈ , Munehide Matsuhisa ₈ , Taka-Aki Matsuoka ₉ , Tetsuya Yamada ₂ , Hirotaka Watada _{3,

4,

10,

11} , Yoshio Fujitani ₁

Affiliation

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.
Department of Metabolism & Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan.
Center for Therapeutic Innovations in Diabetes, Juntendo University Graduate School of Medicine, Tokyo, Japan.
Department of Physiology, Faculty of Medicine, Saitama Medical University, Saitama, Japan.
Institute for Research Initiatives, Nara Institute of Science and Technology (NAIST), Nara, Japan.
Bio-science Research Center, Kyoto Pharmaceutical University, Kyoto, Japan.
Diabetes Therapeutics and Research Center, Institute of Advanced Medical Sciences, Tokushima University, Tokushima, Japan.
The First Department of Medicine, Wakayama Medical University, Wakayama, Japan.
Center for Identification of Diabetic Therapeutic Targets, Juntendo University Graduate School of Medicine, Tokyo, Japan.
Sportology Center, Juntendo University Graduate School of Medicine, Tokyo, Japan.

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.

Methods

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 Ca²⁺ imaging. Diabetic conditions were experimentally induced in mice by either streptozotocin or diphtheria toxin.

Results

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 Ca²⁺ 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.

Data availability

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).

Graphical abstract

中文翻译：

Ppy谱系细胞的表征阐明了小鼠胰腺β细胞的功能异质性

目标/假设

分泌 PP（由Ppy基因编码）的胰腺多肽 (PP) 细胞是胰腺内分泌细胞的少数群体。尽管已经报道了 β 细胞身份的丧失可能与 β 到 PP 细胞命运的转换有关，但目前，关于Ppy谱系细胞的特征知之甚少。

方法

我们使用Ppy-Cre驱动小鼠和 PP 特异性单克隆抗体来研究Ppy谱系细胞和β细胞之间的关联。通过单细胞转录组分析研究内分泌细胞的分子谱，通过Ca ²⁺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在小鼠中实验性地诱导糖尿病病症。

结果

发现Ppy谱系细胞有助于四种主要类型的内分泌细胞，包括β细胞。Ppy谱系 β 细胞是一个较小的亚群，占总 β 细胞的 12-15%，并且大部分 (81.2%) 位于胰岛外围。使用Ppy谱系示踪剂的无偏单细胞分析表明，β 细胞由七个簇组成，它们分为两组（即Ppy谱系和非Ppy谱系 β 细胞）。这些β细胞亚群在其功能和基因表达谱方面表现出不同的特征。Ppy谱系 β 细胞具有减少的葡萄糖刺激的 Ca ²⁺信号反应，并且在实验性糖尿病模型中数量增加。