Comparison of the Safety and Efficacy of Hypoxia-Conditioned Mesenchymal Stem Cells and Their Extracellular Vesicles in a Spinal Cord Injury Rat Model.

Abstract

Mesenchymal stem cells (MSCs) and their extracellular vesicles (EVs) have both shown promise in spinal cord injury (SCI) treatment. While hypoxia preconditioning significantly enhances the therapeutic potential of both MSCs and EVs, a comparative analysis of safety and efficacy is still lacking. Given that EVs offer several advantages over MSCs - such as lower immunogenicity and ease of storage and delivery - this study aimed to determine whether hypoxic EVs could serve as a potent alternative to hypoxic MSC therapy. SCI rat models were established using the clip compression method and treated with three intrathecal injections of either hypoxia-preconditioned UC-MSCs (1 × 10⁶ cells) or their EVs (300 µg total protein, equivalent to 4.6 × 10particles). Safety was assessed through clinical observations, biochemical analysis, and histological examination. Therapeutic efficacy was evaluated via behavioral tests, including the BBB score, Rotarod performance, sensory response, bladder function, and spinal cord histopathology. Hypoxic UC-MSCs and their EVs were safe, as no severe side effects were observed in clinical signs, blood parameters, liver and kidney function, or histological evaluations. They were effective in enhancing motor coordination and balance, improving bladder function, reducing spinal cord cavitation, and decreasing inflammatory cell infiltration. Although both treatments contributed to early hindlimb motor function recovery by day 7, only MSCs promoted sustained improvement through day 28. Since hypoxic MSCs demonstrate better effects on hindlimb motor function recovery, EVs may not serve as a complete substitute. Nevertheless, due to their advantages over cell-based therapies, hypoxic MSC-EVs remain strong therapeutic candidates, particularly in situations where cell therapy is not feasible.