Inflammatory Synovial Fibroblast Culture in 3D Systems: A Comparative Transcriptomic and Functional Study

Inflammation is essential for responding to infections and subsequent tissue healing. However, chronic unresolved inflammation can become a serious health problem, as exemplified in the joints during Rheumatoid Arthritis (RA). Why does inflammation persist in RA? The answer could lie with synovial fibroblasts, non-haemopoietic cells that can adopt a pathogenic phenotype that fuels disease progression for years. Critically, targeting local fibroblasts could stop joint inflammation without suppressing systemic immunity. Nevertheless, basic research findings have not been translated to new drugs, perhaps because non-physiological data can be inadvertently generated in 2D cultures. Thus, developing better in vitro platforms is an urgent need in biomedical research. In this work, we sought to understand how distinct 3D environments affect fibroblast-mediated inflammation. Arthritic synovial fibroblasts were expanded and cultured in 2D, 3D rigid scaffolds and engineered hydrogels. The results reveal that SFs are plastic and adopt inflammatory or remission-like phenotypes in response to their surroundings. This work identifies new directions to develop better models for drug testing, and even signposts candidate mechanisms by which to rewire destructive SFs.