A point-of-research decision in synovial tissue engineering: Mesenchymal stromal cells, tissue derived fibroblast or CTGF-mediated mesenchymal-to-fibroblast transition

• Published in: European journal of cell biology 2024-12, Vol.103 (4), p.151455, Article 151455
• Main Authors: Damerau, Alexandra, Kirchner, Marieluise, Mertins, Philipp, Buttgereit, Frank, Gaber, Timo
• Format: Article
• Language: English
• Subjects: Cell Differentiation; Cells, Cultured; Connective Tissue Growth Factor - genetics; Connective Tissue Growth Factor - metabolism; Cytokines; Fibroblasts - metabolism; Humans; Male; Mesenchymal Stem Cells - cytology; Mesenchymal Stem Cells - metabolism; Metabolism; Osteoarthritis; Osteoarthritis - metabolism; Osteoarthritis - pathology; Synovial Membrane - cytology; Synovial Membrane - metabolism; Synovial membrane model; Synoviocytes - metabolism; Tissue Engineering - methods; Trauma-fibroblast
• ISSN: 0171-9335; 1618-1298; 1618-1298
• DOI: 10.1016/j.ejcb.2024.151455

Rheumatoid arthritis (RA) and osteoarthritis (OA) are prevalent inflammatory joint diseases characterized by synovitis, cartilage, and bone destruction. Fibroblast-like synoviocytes (FLSs) of the synovial membrane are a decisive factor in arthritis, making them a target for future therapies. Developing novel strategies targeting FLSs requires advanced in vitro joint models that accurately replicate non-diseased joint tissue. This study aims to identify a cell source reflecting physiological synovial fibroblasts. Therefore, we newly compared the phenotype and metabolism of “healthy” knee-derived FLSs from patients with ligament injuries (trauma-FLSs) to mesenchymal stromal cells (MSCs), their native precursors. We differentiated MSCs into fibroblasts using connective tissue growth factor (CTGF) and compared selected protein and gene expression patterns to those obtained from trauma-FLSs and OA-FLSs. Based on these findings, we explored the potential of an MSC-derived synovial tissue model to simulate a chronic inflammatory response akin to that seen in arthritis. We have identified MSCs as a suitable cell source for synovial tissue engineering because, despite metabolic differences, they closely resemble human trauma-derived FLSs. CTGF-mediated differentiation of MSCs increased HAS2 expression, essential for hyaluronan synthesis. It showed protein expression patterns akin to OA-FLSs, including markers of ECM components and fibrosis, and enzymes leading to a shift in metabolism towards increased fatty acid oxidation. In general, cytokine stimulation of MSCs in a synovial tissue model induced pro-inflammatory and pro-angiogenic gene expression, hyperproliferation, and increased glucose consumption, reflecting cellular response in human arthritis. We conclude that MSCs can serve as a proxy to study physiological synovial processes and inflammatory responses. In addition, CTGF-mediated mesenchymal-to-fibroblast transition resembles OA-FLSs. Thus, we emphasize MSCs as a valuable cell source for tools in preclinical drug screening and their application in tissue engineering. •Human knee-derived FLSs from trauma patients exhibit a stem cell-like phenotype similar to human bone marrow-derived MSCs.•MSCs did not differ substantially in protein expression from trauma-FLSs.•Stimulation with CTGF leads to activation of MSCs and their differentiation into a profibrotic fibroblast phenotype.•Mimicking the 3D geometry of the synovial membrane supports the arrangement of M