Subaxillary implantation of mesenchymal stem cell spheroids is a novel therapy for myocardial ischemia reperfusion injury

Introduction: Mesenchymal stem cell (MSC) transplantation has emerged as a promising therapy for mitigating cardiac remodeling following myocardial infarction/reperfusion (I/R) injury. However, conventional MSC transplantation faces challenges related to poor survival and limited paracrine activity. Objectives: This study aims to investigate the efficacy of a novel approach utilizing MSC spheroids for the treatment of myocardial I/R injury. Specifically, we seek to demonstrate the ability of MSC spheroids to improve cardiac function, reduce infarct size, inhibit fibrosis and inflammation, and modulate oxidative stress post-I/R injury. Methods: MSC spheroids were prepared and subcutaneously implanted in mice subjected to myocardial I/R injury. Cardiac function was assessed, and histological analysis was performed to evaluate infarct size, fibrosis, and inflammatory cell infiltration. Cytokine analysis and quantitative proteomics were conducted to assess alterations in serum cytokine levels and identify cardioprotective proteins secreted by MSC spheroids. Results: MSC spheroids significantly improved impaired cardiac function, surpassing the efficacy of intravascular MSC injection at 2 weeks post-I/R injury. Histological analysis revealed reductions in infarct size and cardiac fibrosis, accompanied by inhibited oxidative stress and inflammatory cell infiltration. Analysis of serum cytokines indicated alterations following MSC spheroid transplantation. Proteomic analysis identified cardioprotective proteins secreted by MSC spheroids, predominantly within extracellular vesicles and enriched in the HIF-1 signaling pathway. Conclusion: Subcutaneous transplantation of MSC spheroids represents a non-invasive, simple, and stable approach for attenuating myocardial I/R injury. Our findings underscore the potential of MSC spheroids to enhance cardiac repair and remodeling, offering promising implications for the clinical management of I/R injury and associated cardiac complications.