Abstract
The study is devoted to the identification of changes in the proteomic profile of senescent mesenchymal stromal cells of adipose tissue, which determine the modulation of the macrophage phenotype and are involved in the pathogenetic cascade of the formation of inflammageing in obesity.
Material and methods. A proteomic analysis of adipogenic MSCs cultured under conditions simulating senescent changes in cells (various oxygen content conditions of 17% O2–7% O2, the use of senescence inducers – doxorubicin 0.2 µg/ml, H2O2 0.35 µg/ml) was performed. The severity of senescent changes was assessed by the classical beta-galactosidase staining method, as well as by the documented markers of senescence CDKN1A and CDKN2A by PCR-RT. Differentially expressed proteins were identified by LC-MS/MS method followed by bioinformatic analysis.
Results. Cell culture under 17% O2 conditions induced a 2.35-fold increase in CDKN1A and 1.52-fold increase in CDKN2A expression relative to 7% O2 and was accompanied by more pronounced changes in cell color for β-galactosidase. Proteomic analysis identified three differentially expressed proteins that significantly determine the phenotypic plasticity of macrophages: S100A6 (↑2,95 log2FC, p=3,43×10-10), A2M (↓1,06 log2FC, p=2,17×10-6) и ITGB1 (↓1,63 log2FC, p=5,29×10-5). Three signaling cascades have been established, which involve the identified proteins: 1) S100A6→RAGE→NF-κB, inducing M1-polarization of macrophages; 2) A2M deficiency, leading to uncontrolled proteolysis with the generation of matrikins and activation of TLR; 3) ITGB1 deficiency, blocking M2-polarization through disruption of the STAT6/PPARγ pathway.
Conclusion. Proteomic reprogramming of senescent MSCs of adipose tissue in obesity is involved in cascading modulation of the macrophage phenotype through SASP-mediated signaling pathways, which contributes to the formation and systemic spread of inflammageing.
Keywords
Authors and affiliations
https://elibrary.ru/woaeds
S.V. Lyamina(1), S.V. Kalish(1), E.O. Kozhevnikova(1), Yu.K. Slepov(1),, N.P. Lyamina(2), S.E. Novikova(3), V.G. Zgoda(3)
1-FSBEI HE “Russian University of Medicine” Healthcare Ministry of Russia, Dolgorukovskaya str., 4, Moscow, 127006,
Russian Federation; 2-State Scientific Center of the Russian Federation, Federal State Budgetary Scientific Institution “
Russian Scientific Center of Surgery named after Academician B.V. Petrovsky” of the Ministry of Education and Science of Russia,
Abrikosovskii per., 2, Moscow, 119435, Russian Federation; 3FSBSI “V.N. Orekhovich Scientific Research Institute
of Biomedical Chemistry”, Pogodinskaya str., 10, b. 8, Moscow, 119121, Russian Federation
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