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In-Depth Analysis of Obesity-Associated Changes in Adipose Tissue-Derived Mesenchymal Stromal/Stem Cells and Primary Cilia Function

ABSTRACT: Adipose tissue-derived mesenchymal stromal/stem cells (ASCs) possess regenerative potential. Obesity induces a pro-inflammatory environment that compromises their function. We investigated how obesity affects ASC biology, focusing on primary cilia. Our data reveal that obesity alters ASC gene expression, particularly in pathways related to the extracellular matrix, transforming growth factor-β (TGFβ) signaling, cell motility, and differentiation. The gene levels of regulatory factor X2 (RFX2) and adenylate cyclase 3 (ADCY3), important for ciliary biogenesis, were downregulated in obese ASCs. TGFβ treatment significantly decreases the expression of RFX2 and ADCY3 in lean ASCs. Knockdown of ADCY3 reduced primary cilium length, whereas pharmacological activation restored it and improved cell motility. These results suggest that obesity impairs ASC ciliary function, contributing to defective adipogenesis and reduced regenerative capacity. Restoring ADCY3 activity partially rescues ciliary integrity and cellular function, highlighting the role of primary cilia in ASC dysfunction and offering potential therapeutic targets for obesity-related disorders.

ORGANISM(S): Homo sapiens

PROVIDER: GSE308101 | GEO | 2025/09/20

REPOSITORIES: GEO

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Project description:Osteoarthritis (OA) is a progressive degenerative joint disorder characterized by chondrocyte dysfunction and extracellular matrix degradation. While stem cell therapies have been constrained by immunological rejection risks, their derived extracellular vesicles (Exos) emerge as a promising alternative therapeutic approach. Antler, a remarkable regenerative organ with extraordinary regenerative capacity and chondrogenic potential, offers a unique biological resource. Antler Stem Cells (ASCs) provide an innovative extracellular vesicle source (ASC-Exos) that presents a compelling therapeutic strategy for addressing OA's complex pathogenesis. To investigate the therapeutic effects and mechanism of ASC-Exos in OA treatment. ASCs characteristics were confirmed through immunofluorescence and tri-lineage differentiation, while exosomes were validated using transmission electron microscopy, nanoparticle tracking analysis, and Western blot. A rat OA model was established to evaluate therapeutic effects of ASC-Exos via different administration routes. Small RNA sequencing identified key extracellular vesicle components, while dual-luciferase reporter assays confirmed regulatory interactions between miR-140 and metalloproteinase-13(MMP13). Stable miR-140 overexpressing ASCs were generated through lentiviral transduction. An IL-1β-stimulated chondrocyte OA model was employed to assess the impact of miR-140-engineered ASC-Exos (miR-140-Exos) on cellular proliferation, migration, and apoptosis. The therapeutic potential was further evaluated in in vivo animal models. We successfully isolated and characterized ASCs and ASC-Exos. Intra-articular injection of ASC-Exos demonstrated superior cartilage repair efficacy. The critical extracellular vesicle component miR-140 was identified. In vitro studies revealed that miR-140-Exos significantly enhanced chondrocyte proliferation and migration while reducing cellular apoptosis. Dual-luciferase assays confirmed miR-140 directly targets MMP13, with MMP13 overexpression partially reversing miR-140-mediated cellular effects. In vivo investigations demonstrated that miR-140-modified ASC-Exos effectively inhibited COL II degradation and suppressed NLRP3 elevation, thereby providing anti-inflammatory benefits and promoting cartilage regeneration. miR-140-Exos represent an innovative therapeutic approach for osteoarthritis, effectively promoting cartilage regeneration and alleviating inflammation through MMP13 inhibition, presenting a novel therapeutic strategy for OA treatment.

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In-Depth Analysis of Obesity-Associated Changes in Adipose Tissue-Derived Mesenchymal Stromal/Stem Cells and Primary Cilia Function

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