Revisiting preclinical and clinical trials of mesenchymal stem cells in heart disease to define a dose response

Bone marrow was identified as a source of hematopoietic and mesenchymal stem cells (MSCs) over 50 years ago, with significant advances in understanding their potential for regenerative medicine. MSCs, discovered to have multipotential capabilities, can differentiate into various cell types and offer therapeutic benefits through multiple mechanisms, including differentiation, paracrine signaling, and immunomodulation. Recent progress in MSC-based therapies has shown promising results in preclinical animal studies, particularly for cardiovascular diseases, which are leading causes of mortality and morbidity worldwide. MSC therapies have emerged as potential treatments for various fibrotic disorders and heart diseases. Both autologous and allogeneic MSCs, derived from sources such as bone marrow and adipose tissue, have demonstrated varying efficacy in clinical trials. MSCs can be administered via different routes, including intravenous and intramyocardial injections, with each method influencing cell engraftment and therapeutic outcomes. However, a critical challenge remains in optimizing the dose-response relationship for MSC therapy. Preclinical studies using small animals have highlighted MSCs' ability to improve cardiac function, reduce infarct size, and enhance myocardial regeneration. Variations in dose, administration route, and cell source significantly impact the outcomes. High doses of MSCs have shown substantial benefits, but excessive doses may lead to diminishing returns or adverse effects. Translational studies in large animal models, such as pigs, have further elucidated these dose-response relationships, revealing that low and high doses can be effective, depending on the specific context. While MSCs offer significant potential in regenerative medicine, particularly for heart disease, a deeper understanding of their mechanisms, optimal dosing, and administration methods is essential. Continued research and clinical trials are needed to refine MSC therapy protocols, address existing inconsistencies, and enhance the overall efficacy of these treatments.