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Leprdb Mouse Model of Type 2 Diabetes: Pancreatic Islet Isolation and Live-cell 2-Photon Imaging Of Intact Islets
Published on: May 11, 2015
ISR inhibition reverses pancreatic β-cell failure in Wolfram syndrome models
Rui Hu1, Xiangyi Chen1, Qiang Su1
1Medical Innovation Center and State Key Laboratory of Cardiology, Translational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.
Abstract:
Pancreatic β-cell failure by WFS1 deficiency is manifested in individuals with wolfram syndrome (WS). The lack of a suitable human model in WS has impeded progress in the development of new treatments. Here, human pluripotent stem cell derived pancreatic islets (SC-islets) harboring WFS1 deficiency and mouse model of β cell specific Wfs1 knockout were applied to model β-cell failure in WS. We charted a high-resolution roadmap with single-cell RNA-seq (scRNA-seq) to investigate pathogenesis for WS β-cell failure, revealing two distinct cellular fates along pseudotime trajectory: maturation and stress branches. WFS1 deficiency disrupted β-cell fate trajectory toward maturation and directed it towards stress trajectory, ultimately leading to β-cell failure. Notably, further investigation of the stress trajectory identified activated integrated stress response (ISR) as a crucial mechanism underlying WS β-cell failure, characterized by aberrant eIF2 signaling in WFS1-deficient SC-islets, along with elevated expression of genes in regulating stress granule formation. Significantly, we demonstrated that ISRIB, an ISR inhibitor, efficiently reversed β-cell failure in WFS1-deficient SC-islets. We further validated therapeutic efficacy in vivo with β-cell specific Wfs1 knockout mice. Altogether, our study provides novel insights into WS pathogenesis and offers a strategy targeting ISR to treat WS diabetes.
Insights
Wolfram syndrome (WS) involves pancreatic beta-cell failure due to WFS1 deficiency. Targeting the integrated stress response (ISR) with ISRIB effectively reversed this failure in stem cell-derived islets and mouse models, offering a new therapeutic strategy for WS diabetes.
Area of Science:
- Cell Biology
- Endocrinology
- Genetics
Background:
- Wolfram syndrome (WS) is characterized by pancreatic beta-cell failure linked to WFS1 deficiency.
- Lack of adequate human models has hindered the development of effective WS treatments.
- Understanding the precise mechanisms of beta-cell failure in WS is crucial for therapeutic innovation.
Purpose of the Study:
- To model beta-cell failure in WS using human pluripotent stem cell-derived islets (SC-islets) and a mouse model.
- To investigate the pathogenesis of WS beta-cell failure using single-cell RNA sequencing (scRNA-seq).
- To identify potential therapeutic targets for WS-associated diabetes.
Main Methods:
- Generation of WFS1-deficient human SC-islets and beta-cell-specific Wfs1 knockout mice.
- High-resolution single-cell RNA sequencing (scRNA-seq) to analyze cellular fate trajectories.
- Investigation of the integrated stress response (ISR) pathway and its modulation by ISRIB.
Main Results:
- WFS1 deficiency redirects beta-cell fate towards a stress trajectory, leading to failure.
- Activated integrated stress response (ISR), specifically aberrant eIF2 signaling, is identified as a key mechanism.
- ISRIB, an ISR inhibitor, successfully reversed beta-cell failure in WFS1-deficient SC-islets and in vivo mouse models.
Conclusions:
- WFS1 deficiency impairs beta-cell function by activating the integrated stress response.
- Targeting the ISR pathway presents a promising therapeutic strategy for Wolfram syndrome diabetes.
- This study provides a novel human stem cell model and mechanistic insights into WS pathogenesis.
