Plaisance Cody, Chow Lyndah, Impastato Renata, Williams Zoë J, Sabino Isabella, Sikes Katie J, Santangelo Kelly S, Dow Steven, Pezzanite Lynn M
Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, United States.
Department of Microbiology, Immunology and Pathology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, United States.
Front Bioeng Biotechnol. 2025 May 22;13:1525969. doi: 10.3389/fbioe.2025.1525969. eCollection 2025.
Intra-articular administration of mesenchymal stromal cells (MSC) has demonstrated anti-inflammatory and chondroprotective activity in both preclinical models and in randomized clinical trials in patients with osteoarthritis (OA). Nonetheless, precedent from MSC studies in non-OA models suggests that the overall anti-inflammatory effectiveness of MSC can be improved by prior immune activation through cytokines or innate immune pathways.
Therefore, in the current study, we determined whether activation of MSC by two different innate immune pathways (Toll-like receptor 3 (TLR3) pathway or Stimulator of Interferon Genes (STING) pathway could improve their effectiveness for intra-articular treatment of OA, using a murine destabilization of the medial meniscus (DMM) model. Outcome parameters included voluntary gait activity, joint histology and RNA transcriptomic analyses of synovial tissues.
We found that activation of MSC via either innate immune pathway improved functional voluntary movement outcomes compared to treatment with non-activated MSC. Moreover, cartilage integrity, including cartilage preservation, was significantly improved in mice receiving activated MSC, with greater benefits observed in animals treated with STING pathway-activated MSC compared to animals treated with non-activated MSC alone. Transcriptomic analysis of joint tissues revealed that treatment with activated MSC upregulated pathways associated with tissue remodeling, angiogenesis, and wound healing compared to tissues from animals treated with non-activated MSC.
These findings indicate therefore that innate immune activation of MSC prior to intra-articular delivery for treatment of OA can significantly improve functional gait activity and chondroprotective effects compared to non-activated MSC and suggest that this strategy could be evaluated clinically.
在骨关节炎（OA）患者的临床前模型和随机临床试验中，关节内注射间充质基质细胞（MSC）已显示出抗炎和软骨保护活性。尽管如此，在非OA模型中进行的MSC研究表明，通过细胞因子或先天免疫途径进行预先免疫激活可以提高MSC的整体抗炎效果。
因此，在本研究中，我们使用小鼠内侧半月板不稳定（DMM）模型，确定通过两种不同的先天免疫途径（Toll样受体3（TLR3）途径或干扰素基因刺激物（STING）途径）激活MSC是否能提高其关节内治疗OA的效果。结果参数包括自主步态活动、关节组织学以及滑膜组织的RNA转录组分析。
我们发现，与未激活的MSC治疗相比，通过任何一种先天免疫途径激活MSC均可改善功能性自主运动结果。此外，接受激活的MSC的小鼠的软骨完整性，包括软骨保存情况，均得到显著改善，与单独接受未激活的MSC治疗的动物相比，接受STING途径激活的MSC治疗的动物表现出更大的益处。关节组织的转录组分析显示，与未激活的MSC治疗的动物的组织相比，激活的MSC治疗上调了与组织重塑、血管生成和伤口愈合相关的途径。
因此，这些发现表明，与未激活的MSC相比，在关节内注射治疗OA之前对MSC进行先天免疫激活可显著改善功能性步态活动和软骨保护作用，并表明该策略可进行临床评估。
