Unique Human and Mouse β-Cell Senescence-Associated Secretory Phenotype (SASP) Reveal Conserved Signaling Pathways and Heterogeneous Factors
- 1 May 2021
- journal article
- research article
- Published by American Diabetes Association in Diabetes
- Vol. 70 (5), 1098-1116
- https://doi.org/10.2337/db20-0553
Abstract
The aging of pancreatic beta-cells may undermine their ability to compensate for insulin resistance, leading to the development of type 2 diabetes (T2D). Aging beta-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 beta-cell failure. In this study, we defined the beta-cell SASP signature based on unbiased proteomic analysis of conditioned media of cells obtained from mouse and human senescent beta-cells and a chemically induced mouse model of DNA damage capable of inducing SASP. These experiments revealed that the beta-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 beta-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 beta-cell subpopulations associated with senescence. Collectively, these results demonstrate the unique secretory profile of senescent beta-cells and its potential implication in health and disease.Other Versions
Funding Information
- institutional startup funds
- National Institutes of Health (P30 DK036836, DK110390)
- Thomas J. Beatson Jr. Foundation (2020-010)
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