Combinatorial transcription factor profiles predict mature and functional human islet α and β cells.

Shristi Shrestha,Xiao-Qing Dai,Jean-Philippe Cartailler,Joan Camunas-Soler,Diane C Saunders,Radhika Aramandla,Stephen C.J Parker,Roland Stein,Patrick E Macdonald,John T Walker,Rita Bottino,Shawn E Levy,Alvin C Powers,Marcela Brissova,Greg Poffenberger,Nripesh Prasad,Rachana Haliyur

doi:10.1172/jci.insight.151621

Abstract

Islet-enriched transcription factors (TFs) exert broad control over cellular processes in pancreatic α and β cells, and changes in their expression are associated with developmental state and diabetes. However, the implications of heterogeneity in TF expression across islet cell populations are not well understood. To define this TF heterogeneity and its consequences for cellular function, we profiled more than 40,000 cells from normal human islets by single-cell RNA-Seq and stratified α and β cells based on combinatorial TF expression. Subpopulations of islet cells coexpressing ARX/MAFB (α cells) and MAFA/MAFB (β cells) exhibited greater expression of key genes related to glucose sensing and hormone secretion relative to subpopulations expressing only one or neither TF. Moreover, all subpopulations were identified in native pancreatic tissue from multiple donors. By Patch-Seq, MAFA/MAFB-coexpressing β cells showed enhanced electrophysiological activity. Thus, these results indicate that combinatorial TF expression in islet α and β cells predicts highly functional, mature subpopulations.

Highlights

Pancreatic islets are cell clusters dispersed throughout the pancreas, composed primarily of endocrine cells that coordinate glucose homeostasis
Transcriptional and immunohistochemical profiling of human α and β cells suggests a role for key transcription factors (TFs) — aristaless related homeobox (ARX), MAFA, and MAFB — in islet cell development and disease
Α cells from donors with type 1 diabetes (T1D) showed decreased ARX expression compared with α cells from nondiabetic donors (Figure 1C), indicating that this factor may contribute to impaired glucagon secretion observed in T1D [17, 18, 40]

Summary

Introduction

Pancreatic islets are cell clusters dispersed throughout the pancreas, composed primarily of endocrine cells that coordinate glucose homeostasis. Islet β cells secrete insulin, which acts to lower blood glucose, and α cells secrete glucagon, which acts to raise blood glucose. Islet α and β cells are characterized by the precise expression of transcriptional and signaling machinery that allows sensing and integration of glucose, nutrient, and neurohormonal signals and proportional response with regulated hormone secretion. Pancreatic islet dysfunction through impaired insulin and/or glucagon secretion is a hallmark of most forms of diabetes [2,3,4,5]. Identifying key factors and molecular pathways governing α and β cell identity and function is crucial to understanding, treating, and preventing diabetes

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