Hydrogen generators-protected mesenchymal stem cells reverse articular redox imbalance-induced immune dysfunction for osteoarthritis treatment

Abstract

Stem cell therapy has revolutionized the management of osteoarthritis (OA), but the articular dysregulated redox status diminishes cell engraftment efficiency and disrupts immune homeostasis, therefore compromising the overall therapeutic efficacy. Here, we present hydrogen (H₂) generators-backpacked mesenchymal stem cells (MSCs) which preserve the biological functions and survival of transplanted cells and reverse articular immune dysfunction, mitigating OA. Specifically, post systemic transplantation, H₂ generators-laden MSCs home to OA joints, and upon stimulation in acidic OA environment, H₂ produced from the generators remodels articular redox balance, thereby relieving the loss of mitochondrial membrane potential, decreasing cell apoptosis rate, and maintaining pluripotent and paracrine functions of MSCs. Furthermore, the reactive oxygen species scavenging by H₂ in combination with paracrine effects of the MSCs promote macrophage polarization towards the anti-inflammatory M2 phenotype, which contributes to reversing synovial immune disorder. In severe OA model, the backpacked MSCs reduce osteoarthritic degeneration, osteophyte formation and joint inflammation, and promote cartilage regeneration. In sum, our work demonstrates that arming with H₂ generators effectively boosts the therapeutic efficacy of MSCs, which hold great potential for alleviating redox imbalance-related tissue lesions, including but not limited to OA.

Keywords: Bioorthogonal chemistry; Hydrogen delivery; Mesenchymal stem cells; Osteoarthritis; Reactive oxygen species.