Single-Cell Transcriptomics Links Loss of Human Pancreatic β-Cell Identity to ER Stress
Nathalie Gröen, Floris Leenders, Ahmed Mahfouz, Amadeo Muñoz García, Mauro J. Muraro, Natascha de Graaf, Ton J. Rabelink, Rob C. Hoeben, Alexander van Oudenaarden, Arnaud Zaldumbide, Marcel Reinders, Eelco J.P. de Koning, Françoise Carlotti
Abstract
The maintenance of pancreatic islet architecture is crucial for proper β-cell function. We previously reported that disruption of human islet integrity could result in altered β-cell identity. Here we combine β-cell lineage tracing and single-cell transcriptomics to investigate the mechanisms underlying this process in primary human islet cells. Using drug-induced ER stress and cytoskeleton modification models, we demonstrate that altering the islet structure triggers an unfolding protein response that causes the downregulation of β-cell maturity genes. Collectively, our findings illustrate the close relationship between endoplasmic reticulum homeostasis and β-cell phenotype, and strengthen the concept of altered β-cell identity as a mechanism underlying the loss of functional β-cell mass.