Unique Human and Mouse β-Cell Senescence-Associated Secretory Phenotype (SASP) Reveal Conserved Signaling Pathways and Heterogeneous Factors
| Autor: | Hui Pan, Cristina Aguayo-Mazzucato, Cristian Abarca, Ayush Midha, Priscila Carapeto, Susan Bonner-Weir, Joshua Andle |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Senescence DNA damage Endocrinology Diabetes and Metabolism 030209 endocrinology & metabolism Biology Transcriptome Mice 03 medical and health sciences Paracrine signalling 0302 clinical medicine Downregulation and upregulation Insulin-Secreting Cells Cellular stress response Internal Medicine Animals Humans Cellular Senescence fungi Phenotype Cell biology 030104 developmental biology Islet Studies Diabetes Mellitus Type 2 Signal transduction Biomarkers DNA Damage Signal Transduction |
| Zdroj: | Diabetes |
| ISSN: | 1939-327X 0012-1797 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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