The beneficial effects of mesenchymal stem cells and their exosomes on myocardial infarction and critical considerations for enhancing their efficacy

Mesenchymal stem cells (MSCs) are multipotent stromal cells with regenerative, anti-inflammatory, and immunomodulatory properties. MSCs and their exosomes significantly improved structural and functional al-terations after myocardial infarction (MI) in preclinical studies and clinical trials. By reprograming intracellular signaling pathways, MSCs attenuate inflammatory response, oxidative stress, apoptosis, pyroptosis, and endo-plasmic reticulum (ER) stress and improve angiogenesis, mitochondrial biogenesis, and myocardial remodeling after MI. MSC-derived exosomes contain a mixture of non-coding RNAs, growth factors, anti-inflammatory mediators, and anti-fibrotic factors. Although primary results from clinical trials were promising, greater effi-cacies can be achieved by controlling several modifiable factors. The optimum timing of transplantation, route of administration, origin of MSCs, number of doses, and number of cells per dose need to be further investigated by future studies. Newly, highly effective MSC delivery systems have been developed to improve the efficacy of MSCs and their exosomes. Moreover, MSCs can be more efficacious after being pretreated with non-coding RNAs, growth factors, anti-inflammatory or inflammatory mediators, and hypoxia. Similarly, viral vector-mediated overexpression of particular genes can augment the protective effects of MSCs on MI. Therefore, future clin-ical trials must consider these advances in preclinical studies to properly reflect the efficacy of MSCs or their exosomes for MI.