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; Maria Hatzoglou

doi:10.1038/s41467-022-32425-7

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 TiroshFeyza Engin^*, Maria Hatzoglou^*

^*Corresponding author for this work

School of Pharmacy

Research output: Contribution to journal › Article › peer-review

41 Scopus citations

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.

Original language	English
Article number	4621
Journal	Nature Communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-32425-7
State	Published - 8 Aug 2022

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Publisher Copyright:
© 2022, The Author(s).

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Chen, C. W., Guan, B. J., Alzahrani, M. R., Gao, Z., Gao, L., Bracey, S., Wu, J., Mbow, C. A., Jobava, R., Haataja, L., Zalavadia, A. H., Schaffer, A. E., Lee, H., LaFramboise, T., Bederman, I., Arvan, P., Mathews, C. E., Gerling, I. C., Kaestner, K. H., ... Hatzoglou, M. (2022). Adaptation to chronic ER stress enforces pancreatic β-cell plasticity. Nature Communications, 13(1), Article 4621. https://doi.org/10.1038/s41467-022-32425-7

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title = "Adaptation to chronic ER stress enforces pancreatic β-cell plasticity",

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.",

author = "Chen, {Chien Wen} and Guan, {Bo Jhih} and Alzahrani, {Mohammed R.} and Zhaofeng Gao and Long Gao and Syrena Bracey and Jing Wu and Mbow, {Cheikh A.} and Raul Jobava and Leena Haataja and Zalavadia, {Ajay H.} and Schaffer, {Ashleigh E.} and Hugo Lee and Thomas LaFramboise and Ilya Bederman and Peter Arvan and Mathews, {Clayton E.} and Gerling, {Ivan C.} and Kaestner, {Klaus H.} and Boaz Tirosh and Feyza Engin and Maria Hatzoglou",

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year = "2022",

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doi = "10.1038/s41467-022-32425-7",

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Chen, CW, Guan, BJ, Alzahrani, MR, Gao, Z, Gao, L, Bracey, S, Wu, J, Mbow, CA, Jobava, R, Haataja, L, Zalavadia, AH, Schaffer, AE, Lee, H, LaFramboise, T, Bederman, I, Arvan, P, Mathews, CE, Gerling, IC, Kaestner, KH, Tirosh, B, Engin, F & Hatzoglou, M 2022, 'Adaptation to chronic ER stress enforces pancreatic β-cell plasticity', Nature Communications, vol. 13, no. 1, 4621. https://doi.org/10.1038/s41467-022-32425-7

TY - JOUR

T1 - Adaptation to chronic ER stress enforces pancreatic β-cell plasticity

AU - Chen, Chien Wen

AU - Guan, Bo Jhih

AU - Alzahrani, Mohammed R.

AU - Gao, Zhaofeng

AU - Gao, Long

AU - Bracey, Syrena

AU - Wu, Jing

AU - Mbow, Cheikh A.

AU - Jobava, Raul

AU - Haataja, Leena

AU - Zalavadia, Ajay H.

AU - Schaffer, Ashleigh E.

AU - Lee, Hugo

AU - LaFramboise, Thomas

AU - Bederman, Ilya

AU - Arvan, Peter

AU - Mathews, Clayton E.

AU - Gerling, Ivan C.

AU - Kaestner, Klaus H.

AU - Tirosh, Boaz

AU - Engin, Feyza

AU - Hatzoglou, Maria

PY - 2022/8/8

Y1 - 2022/8/8

N2 - 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.

AB - 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.

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Adaptation to chronic ER stress enforces pancreatic β-cell plasticity

Abstract

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