Center for Joint Surgery, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing, 400038, China.
Mol Biol Rep. 2024 Apr 20;51(1):550. doi: 10.1007/s11033-024-09499-1.
The therapeutic efficacy of intra-articular mesenchymal stem cells (MSCs) injection for patients with osteoarthritis (OA) currently exhibits inconsistency, and the underlying mechanism remains elusive. It has been postulated that the immunomodulatory properties and paracrine activity of MSCs might be influenced by the inflammatory micro-environment within osteoarthritic joints, potentially contributing to this observed inconsistency.
Adipose-derived MSCs (ADSCs) were isolated from SD rats and pre-treated with Toll-like receptor 3 (TLR3) agonist Poly I:C or Toll-like receptor 4 (TLR4) agonist LPS. The pre-treated ADSCs were then co-cultured with IL-1β-induced osteoarthritic chondrocytes using a Transwell system to analyze the paracrine effect of ADSCs on reversing the osteoarthritic phenotype of chondrocytes.
RT-PCR and Western blot analysis revealed that Poly I:C and LPS pre-treatments up-regulated the expression of IL-10 and IL-6 in ADSCs, respectively. Furthermore, only Poly I:C-preconditioned ADSCs significantly promoted proliferation while inhibiting apoptosis in IL-1β-treated chondrocytes. Additionally, Poly I:C-preconditioned ADSCs downregulated MMP13 expression while upregulating aggrecan and collagen II expression levels in IL-1β-treated chondrocytes.
TLR3 activation polarizes ADSCs into an immunomodulatory phenotype distinct from TLR4 activation, exerting differential effects on reversing the osteoarthritic phenotype of chondrocytes; thus indicating that MSCs' paracrine effect regulated by TLRs signaling impacts the efficacy of intra-articular MSCs injection.
关节内间充质干细胞（MSCs）注射治疗骨关节炎（OA）患者的疗效目前存在不一致性，其潜在机制尚不清楚。据推测，MSCs 的免疫调节特性和旁分泌活性可能受到 OA 关节内炎症微环境的影响，这可能是导致这种观察到的不一致性的原因之一。
从 SD 大鼠中分离脂肪来源的间充质干细胞（ADSCs），并用 Toll 样受体 3（TLR3）激动剂 Poly I:C 或 Toll 样受体 4（TLR4）激动剂 LPS 预处理 ADSCs。然后将预处理的 ADSCs 与 IL-1β 诱导的 OA 软骨细胞在 Transwell 系统中共培养，分析 ADSCs 对逆转软骨细胞 OA 表型的旁分泌作用。
实时定量 PCR 和 Western blot 分析显示，Poly I:C 和 LPS 预处理分别上调了 ADSCs 中 IL-10 和 IL-6 的表达。此外，只有 Poly I:C 预处理的 ADSCs 显著促进了 IL-1β 处理的软骨细胞的增殖，同时抑制了其凋亡。此外，Poly I:C 预处理的 ADSCs 下调了 MMP13 的表达，同时上调了 IL-1β 处理的软骨细胞中聚集蛋白聚糖和胶原 II 的表达水平。
TLR3 激活将 ADSCs 极化为一种与 TLR4 激活不同的免疫调节表型，对逆转软骨细胞的 OA 表型产生不同的影响；这表明 TLRs 信号调节的 MSCs 旁分泌作用影响关节内 MSCs 注射的疗效。
