Single-Cell Transcriptomics Links Loss of Human Pancreatic β-Cell Identity to ER Stress

Nathalie Groen; Floris Leenders; Ahmed Mahfouz; Amadeo Munoz-Garcia; Mauro J Muraro; Natascha de Graaf; Ton J Rabelink; Rob Hoeben; Alexander van Oudenaarden; Arnaud Zaldumbide; Marcel J T Reinders; Eelco J P de Koning; Françoise Carlotti

doi:10.3390/cells10123585

Single-Cell Transcriptomics Links Loss of Human Pancreatic β-Cell Identity to ER Stress

Nathalie Groen
, Floris Leenders
, Ahmed Mahfouz
, Amadeo Munoz-Garcia
, Mauro J Muraro
, Natascha de Graaf
, Ton J Rabelink
, Rob Hoeben
, Alexander van Oudenaarden
, Arnaud Zaldumbide
, Marcel J T Reinders
, Eelco J P de Koning
, Françoise Carlotti

Hubrecht Institute

Leiden University Medical Center
Hubrecht Institute - Royal Netherlands Academy of Arts and Sciences (KNAW), University Medical Centre Utrecht, Utrecht, Netherlands.
Molecular Cytogenetics Group, Human Cancer Genetics Program, Spanish National Cancer Research Center (CNIO), Madrid, Spain.
University Medical Center Utrecht.
Department of Internal Medicine, Radboud University Medical Center, Nijmegen, Netherlands.

Research output: Contribution to journal/periodical › Article › Scientific › peer-review

12 Citations (Scopus)

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.

Original language	English
Journal	Cells
Volume	10
Issue number	12
DOIs	https://doi.org/10.3390/cells10123585
Publication status	Published - 19 Dec 2021

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title = "Single-Cell Transcriptomics Links Loss of Human Pancreatic β-Cell Identity to ER Stress",

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.",

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month = dec,

day = "19",

doi = "10.3390/cells10123585",

language = "English",

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TY - JOUR

T1 - Single-Cell Transcriptomics Links Loss of Human Pancreatic β-Cell Identity to ER Stress

AU - Groen, Nathalie

AU - Leenders, Floris

AU - Mahfouz, Ahmed

AU - Munoz-Garcia, Amadeo

AU - Muraro, Mauro J

AU - de Graaf, Natascha

AU - Rabelink, Ton J

AU - Hoeben, Rob

AU - van Oudenaarden, Alexander

AU - Zaldumbide, Arnaud

AU - Reinders, Marcel J T

AU - Koning, Eelco J P de

AU - Carlotti, Françoise

PY - 2021/12/19

Y1 - 2021/12/19

N2 - 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.

AB - 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.

U2 - 10.3390/cells10123585

DO - 10.3390/cells10123585

M3 - Article

C2 - 34944092

SN - 2073-4409

VL - 10

JO - Cells

JF - Cells

IS - 12

ER -

Single-Cell Transcriptomics Links Loss of Human Pancreatic β-Cell Identity to ER Stress

Abstract

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