A Multi-Omics Approach Reveals Interleukin 1 Beta Priming as a Key Driver of Immunomodulatory and Regenerative Programs in Adipose-Derived Stem Cells for Osteoarthritis Therapy.

Osteoarthritis is a chronic degenerative joint disease characterized by inflammation and cartilage degradation, for which current treatments are mainly symptomatic and unable to halt disease progression. Adipose-derived mesenchymal stem cells (ASCs) represent a promising therapeutic option due to their regenerative and immunomodulatory properties, which may be further enhanced through specific priming strategies. In this study, primary human ASCs were exposed to interleukin-1 beta (IL1β), interferon-gamma (IFNγ), or hypoxic priming, and subsequently analyzed using a multi-omics approach integrating RNA sequencing, proteomics of secretome, and exosomal miRNA profiling. Differential gene expression, protein abundance, and miRNA signatures were assessed together with functional enrichment and network analyses. IL1β priming induced marked transcriptional reprogramming of ASCs, while hypoxia and IFNγ priming produced limited changes. IL1β also profoundly reshaped the ASC secretome and exosomal miRNA cargo, revealing coordinated regulation of pathways involved in immune modulation and cartilage remodeling. In contrast, the other priming conditions showed minimal and less integrated molecular effects. Overall, IL1β priming consistently generated a multi-layered molecular signature linking immunoregulatory and regenerative pathways. These findings suggest that IL1β priming enhances the functional properties of ASCs and provides mechanistic insight supporting their potential use in osteoarthritis therapy.