Single-cell transcriptomics links loss of human pancreatic β-cell identity to er stress
Nathalie Groen (Leiden University Medical Center)
Floris Leenders (Leiden University Medical Center)
Ahmed Mahfouz (TU Delft - Pattern Recognition and Bioinformatics, Leiden University Medical Center)
Amadeo Munoz-Garcia (Leiden University Medical Center)
Mauro J. Muraro (University Medical Center Utrecht)
Natascha de Graaf (Leiden University Medical Center)
Ton J. Rabelink (Leiden University Medical Center)
Rob Hoeben (Leiden University Medical Center)
Marcel J.T. Reinders (Leiden University Medical Center, TU Delft - Pattern Recognition and Bioinformatics)
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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 illus-trate 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.
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