# Comparative efficacy of different doses of mesenchymal stem cells derived from different tissue sources for knee osteoarthritis: a systematic review and network meta-analysis of randomized controlled trials

## TL;DR

This study compares different doses and tissue sources of mesenchymal stem cells for knee osteoarthritis treatment, finding moderate-dose adipose-derived cells most effective with balanced safety.

## Contribution

The study provides the first network meta-analysis comparing MSC doses and tissue sources for KOA, identifying optimal efficacy and safety profiles.

## Key findings

- Moderate-dose adipose-derived MSCs (M_ADSCS) showed the greatest long-term improvements in pain and joint function with balanced safety.
- High-dose adipose-derived MSCs provided superior short-term pain relief but increased adverse events.
- Adipose-derived MSCs demonstrated stronger anti-inflammatory and immunomodulatory effects compared to other sources.

## Abstract

Knee osteoarthritis (KOA) remains a leading cause of disability, and mesenchymal stem cells (MSCs) show potential for KOA treatment. However, existing studies demonstrate conflicting results on the optimal dose and tissue source of MSCs for KOA treatment. This gap limits evidence-based treatment decisions.

A network meta-analysis (NMA) was conducted to evaluate the efficacy and safety of MSCs at different doses and from tissue sources in treating KOA. Randomized controlled trials (RCTs) were searched up to November 12, 2025. MSC doses were categorized into low ((0 < 20) ×106), moderate ((20 ≤ cells < 50) ×106), and high (cells ≥ 50 ×106). 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.

A total of 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_ADSCS) showed superior efficacy at 3 months, while moderate-dose adipose-derived MSCs (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 adipose-derived MSCs (ADSCS), as well as low-dose bone-derived MSCs (L_BMSCS), with M_ADSCS showing the greatest benefit. Low-dose ADSCS (L_ADSCS) had a significantly low risk of AEs.

Eleven RCTs involving 602 participants were analyzed. M_ADSCS showed the greatest long-term improvements in pain (VAS) and joint function (WOMAC), with balanced efficacy and safety. High-dose ADSCS provided superior short-term analgesia but induced more adverse events, likely due to cell overcrowding and microenvironmental stress. Molecular evidence suggests that ADSCS exert stronger anti-inflammatory and immunomodulatory effects than MSCs from 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.

This NMA identifies M_ADSCS as the most effective MSC treatment for KOA, with balanced efficacy and safety profiles. These findings provide valuable insights for optimizing MSC therapy and highlight the need for further research on dosing and tissue sources.