Insights into mesenchymal stem/stromal cell conditioned media as a long-lasting treatment for pain and psychiatric comorbidities in a murine model of osteoarthritis.

Abstract

Osteoarthritis (OA) is a prevalent musculoskeletal condition characterized by chronic pain and often accompanied by psychiatric comorbidities, such as anxiety and depression. The mesenchymal/stromal cell (MSC) secretome has emerged as promising therapy due to its immunomodulatory and regenerative properties. This study aimed to compare the therapeutic efficacy of standard (CM) and cytokine-primed conditioned media (CM) derived from human adipose-derived MSCs in mitigating pain, mood alterations and neuroinflammation in a murine OA model. OA was induced by intra-articular injection of monoiodoacetate in male C57BL/6J mice. On day 7, mice received a single intravenous dose of CM or CMat two concentrations. Pain-related behavior was assessed by mechanical and thermal nociceptive tests. Anxiety- and depression-like behaviors were evaluated through open field, light/dark box, and forced swim tests. Pro- and anti-inflammatory cytokines and (neuro)inflammatory markers were analyzed in OA joint, and in the peripheral and central nervous system. Peripheral innervation and substance P were assessed in OA paw skin. Both CM and CMreduced painful and affective symptoms in a dose-dependent manner. However, CM (from non-primed MSCs) exhibited faster onset and longer-lasting effects, up to 17 days post-injection, compared to CM. CM also led to greater improvements in neuroinflammatory profiles, rebalancing cytokine pattern and macrophage polarization across peripheral and central tissues. MSC secretome, especially when generated without inflammatory priming, represents a safe and long-lasting therapeutic option for OA pain and associated mood disorders. These findings highlight its clinical potential as an innovative multi-targeted biological therapy.