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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 2021-03-05, 22:17 authored by Ayush Midha, Hui Pan, Cristian Abarca, Joshua Andle, Priscila Carapeto, Susan Bonner-Weir, Cristina Aguayo-MazzucatoThe 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.