Abstract

Introduction: Knee osteoarthritis (KOA) remains a leading cause of disability, with mesenchymal stem cells (MSCs) showing potential for treatment. However, the optimal dose and tissue source of MSCs for KOA remain unclear, with existing studies offering conflicting results. This gap limits clinicians’ ability to make evidence-based treatment decisions.

Materials& Methods: We conducted a network meta-analysis (NMA) to evaluate the efficacy and safety of MSCs from different doses and tissue sources in treating KOA. We searched for randomized controlled trials (RCTs) up to December 1, 2024, categorizing MSC doses into low [(0 ＜ 20) ×10 6 ], moderate [(20 ≤ cells ＜ 50) ×10 6 ], and high [cells ≥ 50 ×10 6 ]. Efficacy was assessed using Visual Analog Scale (VAS) scores, Western Ontario and McMaster Universities Arthritis Index (WOMAC) scores, and adverse events ( AEs) at 3, 6, and 12 months.

Results: 11 RCTs were included. Except for moderate-dose bone-derived MSCs (M_BMSCS), all treatment groups significantly improved VAS scores at 3, 6, and 12 months. High-dose adipose-derived MSCs (H_ H_ADSCS) showed superior efficacy at 3 months, while moderate-dose ADSCS (M_ADSCS) was most effective at 6 and 12 months. For WOMAC scores, significant improvements were seen at 12 months for high-dose, moderate-dose, and low-dose ADSCS, as well as low-dose BMSC S(L_BMSCS), with M_ ADSCS showing the greatest benefit. L_ ADSCS had a significantly low risk of AEs.

Discussion: Eleven RCTs involving 602 participants were analyzed. Moderate-dose adipose-derived MSCs (M_ADSCS) showed the greatest long-term improvements in pain (VAS) and joint function (WOMAC), balancing efficacy and safety. High-dose ADSCS provided superior short-term analgesia but were associated with higher adverse events, likely due to cell overcrowding and microenvironmental stress. Molecular evidence suggests ADSCS exert stronger anti-inflammatory and immunomodulatory effects than other sources. Variability in dose-response relationships indicates that better MSC dosing may depend on disease severity and patient factors such as BMI and comorbidities. Further large-scale, standardized RCTs are needed to refine dosing strategies and optimize MSC therapy for KOA.

Conclusions: This NMA identifies M_ ADSCS as the most effective MSC treatment for KOA, offering a balance of efficacy and safety. These findings provide valuable insights for optimizing MSC therapy and highlight the need for further research on dosing and tissue source variations.