Obesity drives adipose-derived stem cells into a senescent and dysfunctional phenotype associated with P38MAPK/NF-KB axis

Abstract Background Adipose-derived stem cells (ADSC) are multipotent cells implicated in tissue homeostasis. Obesity represents a chronic inflammatory disease associated with metabolic dysfunction and age-related mechanisms, with progressive accumulation of senescent cells and compromised ADSC func...

Full description

Saved in:

Bibliographic Details
Published in:	Immunity & ageing Vol. 20; no. 1; pp. 1 - 51
Main Authors:	Grun, L K, Maurmann, R M, Scholl, J N, Fogaça, M E, Schmitz, C R R, Dias, C K, Gasparotto, J, Padoin, A V, Mottin, C C, Klamt, F, Figueiró, F, Jones, M H, Filippi-Chiela, E C, Guma, F C R, Barbé-Tuana, F M
Format:	Journal Article
Language:	English
Published:	London BioMed Central Ltd 11-10-2023 BioMed Central BMC
Subjects:	Age Aging Apoptosis Body fat Cell cycle Chronic inflammation Comparative analysis Cyclin-dependent kinase inhibitor p21 Cyclin-dependent kinases Depolarization Gene expression Genetic aspects Genotype & phenotype Homeostasis Inflammatory diseases INK4a protein Insulin resistance Kinases Mesenchymal stem cell Metabolic syndrome Mitochondria NF-κB protein Obesity Oxygen consumption p16 Protein Phenotypes Phosphorylation Plasma Scientific equipment and supplies industry Senescence Stem cells Superoxide Trf1 protein β-Galactosidase Brazil Canada United States
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	Abstract Background Adipose-derived stem cells (ADSC) are multipotent cells implicated in tissue homeostasis. Obesity represents a chronic inflammatory disease associated with metabolic dysfunction and age-related mechanisms, with progressive accumulation of senescent cells and compromised ADSC function. In this study, we aimed to explore mechanisms associated with the inflammatory environment present in obesity in modulating ADSC to a senescent phenotype. We evaluated phenotypic and functional alterations through 18 days of treatment. ADSC were cultivated with a conditioned medium supplemented with a pool of plasma from eutrophic individuals (PE, n = 15) or with obesity (PO, n = 14), and compared to the control. Results Our results showed that PO-treated ADSC exhibited decreased proliferative capacity with G2/M cycle arrest and CDKN1A (p21 WAF1/Cip1 ) up-regulation. We also observed increased senescence-associated β-galactosidase (SA-β-gal) activity, which was positively correlated with TRF1 protein expression. After 18 days, ADSC treated with PO showed augmented CDKN2A (p16 INK4A ) expression, which was accompanied by a cumulative nuclear enlargement. After 10 days, ADSC treated with PO showed an increase in NF-κB phosphorylation, while PE and PO showed an increase in p38MAPK activation. PE and PO treatment also induced an increase in senescence-associated secretory phenotype (SASP) cytokines IL-6 and IL-8. PO-treated cells exhibited decreased metabolic activity, reduced oxygen consumption related to basal respiration, increased mitochondrial depolarization and biomass, and mitochondrial network remodeling, with no superoxide overproduction. Finally, we observed an accumulation of lipid droplets in PO-treated ADSC, implying an adaptive cellular mechanism induced by the obesogenic stimuli. Conclusions Taken together, our data suggest that the inflammatory environment observed in obesity induces a senescent phenotype associated with p38MAPK/NF-κB axis, which stimulates and amplifies the SASP and is associated with impaired mitochondrial homeostasis.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1742-4933 1742-4933
DOI:	10.1186/s12979-023-00378-0