Cord blood mesenchymal stromal cells combined with hyaluronic acid show symptom-modifying and potential disease-modifying effects in an equine osteoarthritis fetlock chip model.

Overview

• This study investigated the effects of combining cord blood-derived mesenchymal stromal cells (eCB-MSCs) with hyaluronic acid (HA) on osteoarthritis (OA) in horses, aiming to assess both symptom relief and potential disease modification.
• Using an equine fetlock osteoarthritis model, they evaluated clinical outcomes, imaging findings, and immune responses after treatment compared to saline controls.

Background and Rationale

• Osteoarthritis in horses causes lameness and declining joint function, severely impacting performance and welfare.
• Traditional therapies primarily address symptoms (pain, inflammation) but do not significantly alter disease progression or joint damage.
• Mesenchymal stromal cells (MSCs) are being explored as biologic treatments that may modify disease by promoting repair and modulating immune responses.
• Equine umbilical cord blood-derived MSCs (eCB-MSCs) are particularly attractive due to easy collection, proliferative capacity, and immunomodulatory properties.
• Hyaluronic acid (HA) is commonly used in joint disease therapy for its lubricating and anti-inflammatory effects and may enhance MSC activity when combined.

Study Design and Methods

• A prospective, randomized experimental study was conducted on twelve Standardbred horses.
• Osteoarthritis was surgically induced by creating an osteochondral (OC) fragment on the proximal phalanx (P1) in one front fetlock joint.
• Six weeks after surgery, horses were randomized to receive an intra-articular injection of either pooled cryopreserved eCB-MSCs combined with HA or saline (control).
• Twelve weeks after initial surgery, a second arthroscopic procedure was done to sample joint tissues and score joint health.
• Clinical lameness was evaluated using both subjective scoring methods and objective gait analysis with inertial sensors.
• Structural disease progression was examined through radiography and high-field MRI, employing a modified Whole-Organ Magnetic Resonance Imaging Score (WORMS) system for detailed assessment.
• Synovial fluid samples were collected longitudinally to quantify cytokines and chemokines, providing insight into inflammatory and immune responses.
• Statistical analyses involved mixed models and non-parametric tests to identify treatment effects and interactions involving pre-treatment inflammation levels and fragment size.

Key Findings

• Safety:
  • Both eCB-MSC+HA and saline treatments were well tolerated without significant adverse joint reactions.
• Clinical Outcomes:
  • Horses receiving eCB-MSC+HA showed significantly improved lameness scores in both objective gait analysis and subjective clinical assessment compared to saline controls.
• Imaging Results:
  • MRI findings demonstrated stabilization or improvement in WORMS scores in the eCB-MSC+HA treated group, whereas the saline group showed progression of joint structural deterioration.
  • Radiographic and arthroscopic scores did not show significant differences between treatment groups, possibly due to the lesser sensitivity of these modalities or short follow-up time.
• Immune and Biomarker Responses:
  • Synovial fluid cytokine levels were influenced by baseline inflammation status and OC fragment size.
  • In the eCB-MSC+HA group, pro-inflammatory cytokines such as IL-1β and TNF-alpha were reduced, while regulatory immune signaling pathways were maintained or enhanced.
  • Pre-treatment WORMS MRI scores correlated with various cytokine levels, linking structural joint damage and immune environment.

Interpretation and Implications

• The combination of eCB-MSCs with HA demonstrated safety and beneficial effects on clinical symptoms of osteoarthritis in this equine model.
• Improved MRI outcomes support the potential disease-modifying capability of this treatment, as it may slow or reverse structural joint damage.
• The immunomodulatory effects observed suggest that eCB-MSC+HA can attenuate harmful inflammation while promoting regulatory pathways contributing to joint health.
• Differences were more evident with MRI than with radiography or arthroscopy, highlighting the higher sensitivity of MRI in detecting early structural changes.
• The study’s small sample size and relatively short duration are limitations; longer-term and larger studies are needed to confirm these promising results and optimize treatment protocols.

Conclusions

• Pooled cryopreserved equine umbilical cord blood-derived MSCs combined with hyaluronic acid safely improve lameness and appear to modify disease progression in early equine osteoarthritis.
• This supports the potential of eCB-MSC+HA as both a symptom-modifying and disease-modifying therapeutic option for equine OA.
• Future research should focus on confirming these effects in larger cohorts and exploring long-term outcomes as well as mechanisms of action.