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

Autor: Grun LK; Graduate Program in Pediatrics and Child Health, School of Medicine, Pontifical Catholic University at Rio Grande do Sul (PUCRS), Porto Alegre, Brazil. lucas.grun@pucrs.br.; Group of Inflammation and Cellular Senescence, Immunobiology Laboratory, School of Health Sciences and Life, Pontifical Catholic University at Rio Grande do Sul (PUCRS), Porto Alegre, Brazil. lucas.grun@pucrs.br., Maurmann RM; Graduate Program in Cellular and Molecular Biology, School of Health, Sciences, and Life, Pontifical Catholic University at Rio Grande do Sul (PUCRS), Porto Alegre, Brazil.; Group of Inflammation and Cellular Senescence, Immunobiology Laboratory, School of Health Sciences and Life, Pontifical Catholic University at Rio Grande do Sul (PUCRS), Porto Alegre, Brazil., Scholl JN; Graduate Program in Biological Sciences: Biochemistry, Federal University at Rio Grande do Sul (UFRGS), Porto Alegre, Brazil., Fogaça ME; Group of Inflammation and Cellular Senescence, Immunobiology Laboratory, School of Health Sciences and Life, Pontifical Catholic University at Rio Grande do Sul (PUCRS), Porto Alegre, Brazil., Schmitz CRR; Group of Inflammation and Cellular Senescence, Immunobiology Laboratory, School of Health Sciences and Life, Pontifical Catholic University at Rio Grande do Sul (PUCRS), Porto Alegre, Brazil.; Graduate Program in Biological Sciences: Biochemistry, Federal University at Rio Grande do Sul (UFRGS), Porto Alegre, Brazil., Dias CK; Graduate Program in Biological Sciences: Biochemistry, Federal University at Rio Grande do Sul (UFRGS), Porto Alegre, Brazil., Gasparotto J; Institute of Biomedical Sciences, Federal University at Alfenas, Alfenas, Brazil., Padoin AV; Graduate Program in Medicine and Health Sciences, Pontifical Catholic University at Rio Grande do Sul (PUCRS), Porto Alegre, Brazil., Mottin CC; Graduate Program in Medicine and Health Sciences, Pontifical Catholic University at Rio Grande do Sul (PUCRS), Porto Alegre, Brazil., Klamt F; Graduate Program in Biological Sciences: Biochemistry, Federal University at Rio Grande do Sul (UFRGS), Porto Alegre, Brazil., Figueiró F; Graduate Program in Biological Sciences: Biochemistry, Federal University at Rio Grande do Sul (UFRGS), Porto Alegre, Brazil., Jones MH; Graduate Program in Pediatrics and Child Health, School of Medicine, Pontifical Catholic University at Rio Grande do Sul (PUCRS), Porto Alegre, Brazil., Filippi-Chiela EC; Institute of Basic Health Sciences, Department of Morphological Sciences, Federal University at Rio Grande do Sul (UFRGS), Porto Alegre, Brazil.; Experimental Research Center, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.; Center for Biotechnology, Federal University at Rio Grande do Sul (UFRGS), Porto Alegre, Brazil., Guma FCR; Graduate Program in Biological Sciences: Biochemistry, Federal University at Rio Grande do Sul (UFRGS), Porto Alegre, Brazil., Barbé-Tuana FM; Graduate Program in Pediatrics and Child Health, School of Medicine, Pontifical Catholic University at Rio Grande do Sul (PUCRS), Porto Alegre, Brazil.; Graduate Program in Cellular and Molecular Biology, School of Health, Sciences, and Life, Pontifical Catholic University at Rio Grande do Sul (PUCRS), Porto Alegre, Brazil.; Group of Inflammation and Cellular Senescence, Immunobiology Laboratory, School of Health Sciences and Life, Pontifical Catholic University at Rio Grande do Sul (PUCRS), Porto Alegre, Brazil.
Jazyk: angličtina
Zdroj: Immunity & ageing : I & A [Immun Ageing] 2023 Oct 11; Vol. 20 (1), pp. 51. Date of Electronic Publication: 2023 Oct 11.
DOI: 10.1186/s12979-023-00378-0
Abstrakt: 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.
(© 2023. BioMed Central Ltd., part of Springer Nature.)
Databáze: MEDLINE
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