Synergistic Enhancement of Peripheral Nerve Regeneration via Ibudilast-Primed Three-Dimensional Spheroid Culture of Human Adipose-Derived Stem Cells.

Evidence from laboratory and animal studies provides groundwork for understanding mechanisms and potential before human studies continue.

• Level A · Stronger Clinical Evidence
• Level B · Emerging clinical evidence with positive signals
• Level C · Early human research exploring benefits
• Level D · Scientific groundwork from lab and animal studies
• Emerging · Emerging topic under active research

Abstract (original English)

Background : Peripheral nerve regeneration relies on Schwann cell activation and neurotrophic support. Although adipose-derived stem cells (ADSCs) show therapeutic potential through paracrine mechanisms, their clinical application is often limited by donor-dependent heterogeneity in therapeutic efficacy. Accordingly, strategies to standardize and potentiate their secretory function are essential. This study investigated a safety-optimized strategy to achieve this by combining three-dimensional (3D) spheroid culture with ibudilast, a clinically approved phosphodiesterase inhibitor. Methods : Human ADSCs were cultured in 2D or 3D conditions with varying ibudilast concentrations. Safety was confirmed via CCK-8 assays, and trophic factor secretion was quantified by RT-qPCR and ELISA. To rigorously validate functional outcomes, conditioned media were applied to a dual-model system comprising immortalized rat (RSC96) and primary human Schwann cells (HSwCs), assessing migration and the expression of regeneration-associated genes. Results : Ibudilast demonstrated no cytotoxicity. While 3D culture alone enhanced secretion compared to 2D controls, the addition of ibudilast provided a synergistic boost, resulting in a 6- to 14-fold increase in NGF, VEGF, and IGF-1 levels compared to 3D spheroids alone. Notably, conditioned media from these primed spheroids significantly accelerated HSwCs

Evidence level

Evidence from laboratory and animal studies provides groundwork for understanding mechanisms and potential before human studies continue.

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