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Unique Human and Mouse β-cell Senescence-Associated Secretory Phenotype (SASP) Reveal Conserved Signaling Pathways and Heterogeneous Factors

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posted on 05.03.2021, 22:17 by Ayush Midha, Hui Pan, Cristian Abarca, Joshua Andle, Priscila Carapeto, Susan Bonner-Weir, Cristina Aguayo-Mazzucato
The aging of pancreatic β-cells may undermine their ability to compensate for insulin resistance, leading to the development of type 2 diabetes (T2D). Aging β-cells acquire markers of cellular senescence and develop a senescence-associated secretory phenotype (SASP) that can lead to senescence and dysfunction of neighboring cells through paracrine actions, contributing to b-cell failure. Herein, we defined the β-cell SASP signature based on unbiased proteomic analysis of conditioned media of cells obtained from mouse and human senescent β-cells and a chemically-induced mouse model of DNA damage capable of inducing SASP. These experiments revealed that the β-cell SASP is enriched for factors associated with inflammation, cellular stress response, and extracellular matrix remodeling across species. Multiple SASP factors were transcriptionally upregulated in models of β-cell senescence, aging, insulin resistance and T2D. Single-cell transcriptomic analysis of islets from an in vivo mouse model of reversible insulin resistance indicated unique and partly reversible changes in β-cell subpopulations associated with senescence. Collectively, these results demonstrate the unique secretory profile of senescent b-cells and its potential implication in health and disease.

Funding

This study was supported by Institutional Startup Funds to C.A.M. (Joslin Diabetes Center) and NIH grants P30 DK036836 Joslin Diabetes Research Center (Cores; P&F to C.A.M.) and DK110390 (to S.B-W), and Thomas J. Beatson Jr. Foundation Grant #2020-010 (CAM).

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