M2-Macrophage-Induced Chronic Inflammation Promotes Reversible Mesenchymal Stromal Cell Senescence and Reduces Their Anti-Fibrotic Properties

• Published in: International journal of molecular sciences 2023-12, Vol.24 (23), p.17089
• Main Authors: Dyachkova, Uliana, Vigovskiy, Maksim, Basalova, Nataliya, Efimenko, Anastasia, Grigorieva, Olga
• Format: Article
• Language: English
• Subjects: Cell cycle; Cellular Senescence; Chemokines; Cytokines; Ethylenediaminetetraacetic acid; Fibroblasts; Fibrosis; Genotype & phenotype; Growth factors; Humans; Hydrogen Peroxide - pharmacology; Inflammation; Macrophages; Mesenchymal Stem Cells; MicroRNAs; Particle size; Regulation; Senescence; Stem cells; Transforming growth factors; Wound healing
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms242317089

Fibrosis and the associated decline in organ functionality lead to an almost 50% mortality rate in developed countries. Multipotent mesenchymal stromal cells (MSC) were shown to suppress the development and progression of fibrosis through secreted factors including specific non-coding RNAs transferred within extracellular vesicles (EV). However, age-associated chronic inflammation can provoke MSC senescence and change secretome composition, thereby affecting their antifibrotic properties. Alternatively activated macrophages (M2-type) are key players in chronic inflammation that may interact with MSC through paracrine mechanisms and decrease their antifibrotic functions. To confirm this hypothesis, we evaluated the M2-macrophage conditioned medium (CM-M2) effect on human adipose-tissue-derived MSC senescence in vitro. We found that CM-M2, as well as a pro-senescence agent, hydrogen peroxide (H O ), increased p21+-MSC number and secretion of IL-6 and MCP-1, which are considered main senescence-associated secretory phenotype (SASP) components. Thus, both exposures led to the senescent phenotype acquisition of MSC. EV from both CM-M2 and H O -exposed MSC, which showed a decreased effect on the suppression of TGFβ-induced fibroblast-to-myofibroblast differentiation compared to EV from control MSC according to αSMA level and the αSMA+-stress fiber reduction. After two weeks of subsequent cultivation under standard conditions, MSC demonstrated a decrease in senescence hallmarks and fibroblast differentiation suppression via EV. These results suggest that M2-macrophage-induced chronic inflammation can reversibly induce MSC senescence, which reduces the MSC's ability to inhibit fibroblast-to-myofibroblast differentiation.