Improved Functional and Structural Outcomes in Post-Traumatic Osteoarthritis with Immune Licensed Mesenchymal Stromal Cell Therapy

Abstract

Osteoarthritis is a painful and debilitating condition, impacting 655 million people worldwide and 33 million individuals in the US, particularly those >65 years of age. When measured in years lived with disability, knee OA was the 11th largest contributor to disability of 291 diseases evaluated1,2. OA is also common in companion animal species; in horses for example, osteoarthritis (OA) represents one of the most common conditions treated by equine practitioners, estimated to affect up to 2/3 of Thoroughbred racehorses and 80% of horses over 15 years of age3,4. Despite this high prevalence, no approved pharmacological intervention, biological therapy, or procedure prevents or reverses progressive destruction of the degenerative joint. 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 these studies, 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 of the two innate immune pathways 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. Importantly, the transcriptomic analysis also revealed important differences in pathways activated by TLR3 activation and STING activation. 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 both strategies could be evaluated clinically.