Novel Applications of Mesenchymal Stem Cell-derived Exosomes for Myocardial Infarction Therapeutics

Abstract

Cardiovascular diseases (CVDs) are the leading cause of mortality and morbidity globally, representing approximately a third of all deaths every year. The greater part of these cases is represented by myocardial infarction (MI), or heart attack as it is better known, which occurs when declining blood flow to the heart causes injury to cardiac tissue. Mesenchymal stem cells (MSCs) are multipotent stem cells that represent a promising vector for cell therapies that aim to treat MI due to their potent regenerative effects. However, it remains unclear the extent to which MSC-based therapies are able to induce regeneration in the heart and even less clear the degree to which clinical outcomes could be improved. Exosomes, which are small extracellular vesicles (EVs) known to have implications in intracellular communication, derived from MSCs (MSC-Exos), have recently emerged as a novel cell-free vector that is capable of conferring cardio-protection and regeneration in target cardiac cells. In this review, we assess the current state of research of MSC-Exos in the context of MI. In particular, we place emphasis on the mechanisms of action by which MSC-Exos accomplish their therapeutic effects, along with commentary on the current difficulties faced with exosome research and the ongoing clinical applications of stem-cell derived exosomes in different medical contexts.

Keywords: cardiac regeneration; cardioprotection; cardiovascular disease; cell-free therapy; exosomes; extracellular vesicles; mesenchymal stem cells; myocardial infarction.

Figure 1

Biogenesis and features of apoptosis bodies (ABs), microvesicles (MVs), and exosomes. Each of the three classes of extracellular vesicle (EV) are characterised by unique biogenesis pathways, molecular markers, and cargo. ABs emerge as the cytoskeleton of apoptotic cells are disassembled and contain various cellular components such as organelles and nuclear fractions. MVs contain a variety of molecular cargo, including DNA, RNA, and protein, and are produced by the cell membrane budding and fission. Exosomes are the smallest class of EV, and are enriched in DNA, RNA, and proteins, and originate from the multivesicular body (MVB).

Figure 2

Summary of MSC-Exo molecular cargo and its functions in angiogenesis, apoptosis, and immunomodulation. MSC-Exo treatments improve blood vessel neo-formations through the activation of a wide range of pro-angiogenic pathways in ECs. In parallel, anti-apoptotic effects are induced via bioenergetics modification, principally though the PI3K/AKT and mTOR pathways. Finally, MSC-Exos modify the inflammatory and fibrotic immune responses, creating a microenvironment more accommodating to regeneration and healing. A highly diverse set of molecular cargo (almost solely consisted of miRNA and protein factors) is responsible for the cardioprotective and regenerative effects of MSC-Exos.