Damerau Alexandra, Kirchner Marieluise, Mertins Philipp, Buttgereit Frank, Gaber Timo
Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Rheumatology and Clinical Immunology, Berlin, Germany; German Rheumatism Research Centre (DRFZ) Berlin, a Leibniz Institute, Berlin, Germany.
Core Unit Proteomics, Berlin Institute of Health at Charité - Universitätsmedizin Berlin and Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
Eur J Cell Biol. 2024 Dec;103(4):151455. doi: 10.1016/j.ejcb.2024.151455. Epub 2024 Sep 10.
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.
类风湿性关节炎（RA）和骨关节炎（OA）是常见的炎症性关节疾病，其特征为滑膜炎、软骨和骨破坏。滑膜的成纤维样滑膜细胞（FLS）是关节炎的决定性因素，使其成为未来治疗的靶点。开发针对FLS的新策略需要能够准确复制非病变关节组织的先进体外关节模型。本研究旨在确定一种反映生理性滑膜成纤维细胞的细胞来源。因此，我们新比较了来自韧带损伤患者的“健康”膝关节来源的FLS（创伤-FLS）与间充质基质细胞（MSC）及其天然前体细胞的表型和代谢。我们使用结缔组织生长因子（CTGF）将MSC分化为成纤维细胞，并将选定的蛋白质和基因表达模式与从创伤-FLS和OA-FLS获得的模式进行比较。基于这些发现，我们探索了MSC来源的滑膜组织模型模拟类似于关节炎中所见慢性炎症反应的潜力。我们已确定MSC是滑膜组织工程的合适细胞来源，因为尽管存在代谢差异，但它们与人类创伤来源的FLS非常相似。CTGF介导的MSC分化增加了透明质酸合成所必需的HAS2表达。它显示出类似于OA-FLS的蛋白质表达模式，包括细胞外基质成分和纤维化的标志物，以及导致代谢向脂肪酸氧化增加转变的酶。一般来说，滑膜组织模型中细胞因子对MSC的刺激诱导促炎和促血管生成基因表达、过度增殖和葡萄糖消耗增加，反映了人类关节炎中的细胞反应。我们得出结论，MSC可作为研究生理性滑膜过程和炎症反应的替代物。此外，CTGF介导的间充质向成纤维细胞转变类似于OA-FLS。因此，我们强调MSC作为临床前药物筛选工具的宝贵细胞来源及其在组织工程中的应用。
