Adaptation to chronic ER stress enforces pancreatic β-cell plasticity

Chien-Wen Chen (), Bo-Jhih Guan, Mohammed R. Alzahrani, Zhaofeng Gao, Long Gao, Syrena Bracey, Jing Wu, Cheikh A. Mbow, Raul Jobava, Leena Haataja, Ajay H. Zalavadia, Ashleigh E. Schaffer, Hugo Lee, Thomas LaFramboise, Ilya Bederman, Peter Arvan, Clayton E. Mathews, Ivan C. Gerling, Klaus H. Kaestner, Boaz Tirosh, Feyza Engin () and Maria Hatzoglou ()
Additional contact information
Chien-Wen Chen: Case Western Reserve University
Bo-Jhih Guan: Case Western Reserve University
Mohammed R. Alzahrani: Case Western Reserve University
Zhaofeng Gao: Case Western Reserve University
Long Gao: University of Pennsylvania Perelman School of Medicine
Syrena Bracey: Case Western Reserve University
Jing Wu: Case Western Reserve University
Cheikh A. Mbow: Case Western Reserve University
Raul Jobava: Case Western Reserve University
Leena Haataja: University of Michigan Medical Center
Ajay H. Zalavadia: Cleveland Clinic
Ashleigh E. Schaffer: Case Western Reserve University
Hugo Lee: University of Wisconsin-Madison, School of Medicine and Public Health
Thomas LaFramboise: Case Western Reserve University
Ilya Bederman: Case Western Reserve University
Peter Arvan: University of Michigan Medical Center
Clayton E. Mathews: University of Florida College of Medicine
Ivan C. Gerling: University of Tennessee
Klaus H. Kaestner: University of Pennsylvania Perelman School of Medicine
Boaz Tirosh: Case Western Reserve University
Feyza Engin: University of Wisconsin-Madison, School of Medicine and Public Health
Maria Hatzoglou: Case Western Reserve University

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: Abstract Pancreatic β-cells are prone to endoplasmic reticulum (ER) stress due to their role in insulin secretion. They require sustainable and efficient adaptive stress responses to cope with this stress. Whether episodes of chronic stress directly compromise β-cell identity is unknown. We show here under reversible, chronic stress conditions β-cells undergo transcriptional and translational reprogramming associated with impaired expression of regulators of β-cell function and identity. Upon recovery from stress, β-cells regain their identity and function, indicating a high degree of adaptive plasticity. Remarkably, while β-cells show resilience to episodic ER stress, when episodes exceed a threshold, β-cell identity is gradually lost. Single cell RNA-sequencing analysis of islets from type 1 diabetes patients indicates severe deregulation of the chronic stress-adaptation program and reveals novel biomarkers of diabetes progression. Our results suggest β-cell adaptive exhaustion contributes to diabetes pathogenesis.

Date: 2022
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DOI: 10.1038/s41467-022-32425-7

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