Characterization of Ppy-lineage cells clarifies the functional heterogeneity of pancreatic beta cells in mice

Pancreatic polypeptide (PP) cells, which secrete PP encoded by the Ppy gene, is a minor population of endocrine cells in the pancreas. At present, little is known about the characteristics of Ppy-expressing cells. Using a Ppy-Cre driver, here we show that cells of the Ppy lineage contribute to four major types of endocrine cells, including beta cells. Unbiased single-cell analysis with a Ppy-lineage tracer demonstrated that beta cells are composed of seven clusters, which are categorized into two groups; i.e., Ppy-lineage and non-Ppy-lineage beta cells. These subpopulations of beta cells demonstrated distinct characteristics in terms of functionality and gene expression profiles. Ppy-lineage beta cells are less active in glucose-stimulated calcium signaling, are localized at the periphery of islets, and survive for long periods in experimental diabetes models, and sharing various molecular characteristics with PP cells. Our results indicate the unexpected degree of beta-cell heterogeneity defined by Ppy-gene activation, providing valuable insights into the homeostatic regulation of pancreatic islets, and future therapeutic strategies against diabetes. scRNA-seq (10× Genomics Chromium Single Cell 3′ Solution v3.1) of islets from 8-week-old (postnatal day 56) healthy male MIP-GFP; Ppy-Cre; Rosa26-tdTomato mice with a mixed background of C57BL/6J and CD-1.

胰多肽（Pancreatic polypeptide，PP）细胞是胰腺中一类稀有内分泌细胞群体，其分泌由Ppy基因编码的胰多肽。目前，学界对表达Ppy基因的细胞的特征仍缺乏深入了解。本研究借助Ppy-Cre驱动工具，证实Ppy谱系细胞可分化为包括β细胞在内的四类主要内分泌细胞。借助Ppy谱系示踪剂开展的无偏倚单细胞分析显示，β细胞可分为7个亚群，可进一步划分为两类：Ppy谱系β细胞与非Ppy谱系β细胞。这两类β细胞亚群在功能与基因表达谱层面均存在显著差异。Ppy谱系β细胞在葡萄糖刺激下的钙信号通路活性更低，定位于胰岛外周区域，在实验性糖尿病模型中可长期存活，且与PP细胞共享诸多分子特征。本研究结果揭示了由Ppy基因激活所定义的β细胞异质性程度远超此前预期，为胰岛稳态调控研究提供了重要见解，同时也为未来糖尿病治疗策略的开发提供了全新思路。本研究的测序数据来源于8周龄（即出生后第56天）健康雄性混合背景（C57BL/6J与CD-1品系杂交）MIP-GFP; Ppy-Cre; Rosa26-tdTomato小鼠的胰岛，采用10× Genomics Chromium Single Cell 3′ Solution v3.1完成了单细胞RNA测序（scRNA-seq）。