Role of MSC‐derived small extracellular vesicles in tissue repair and regeneration

Abstract

Mesenchymal stem cells (MSCs) are crucial for tissue homeostasis and repair, secreting vesicles to the extracellular environment. Isolated exosomes were shown to affect angiogenesis, immunomodulation and tissue regeneration. Numerous efforts have been dedicated to describe the mechanism of action of these extracellular vesicles (EVs) and guarantee their safety, since the final aim is their therapeutic application in the clinic. The major advantage of applying MSC-derived EVs is their low or inexistent immunogenicity, prompting their use as drug delivery or therapeutic agents, as well as wound healing, different cancer types, and inflammatory processes in the neurological and cardiovascular systems. MSC-derived EVs display no vascular obstruction effects or apparent adverse effects. Their nano-size ensures their passage through the blood–brain barrier, demonstrating no cytotoxic or immunogenic effects. Several in vitro tests have been conducted with EVs obtained from different sources to understand their biology, molecular content, signaling pathways, and mechanisms of action. Application of EVs to human therapies has recently become a reality, with clinical trials being conducted to treat Alzheimer’s disease, retina degeneration, and COVID-19 patients. Herein, we describe and compare the different extracellular vesicles isolation methods and therapeutic applications regarding the tissue repair and regeneration process, presenting the latest clinical trial reports.

Basic Pathogenic Mechanisms and Epigenetic Players Promoted by Extracellular Vesicles in Vascular Damage

“…The EVs’ cargo is known to include proteins and nucleic acids such as DNA, mRNA and a variety of non-coding RNAs (ncRNAs) that, when released in target cells, differentially regulate gene expression [ 23 , 24 , 25 ]. Exosomes not only regulate physiological states, such as tissue regeneration, immune surveillance and stem cell plasticity [ 26 , 27 , 28 , 29 ], but also participate in the pathophysiology of CVD, neurodegenerative diseases and malignant tumors [ 30 , 31 , 32 ] and have potential value for precise diagnosis, prognosis assessment and disease treatment. Moreover, given their biological role, EVs can affect the pathogenesis of CVD and tumor progression [ 33 , 34 , 35 ].…”

Non-Classical Intercellular Communications: Basic Mechanisms and Roles in Biology and Medicine

“…Since extracellular vesicles—in particular, exosomes—have significant biotechnological potential but are also involved in pathogenesis, the study of the mechanisms underlying the maturation and release of exosomes may be important for the development of new therapeutic approaches in medicine. In preclinical trials, the effects of microvesicles and exosomes obtained from conditioned stem cell media are comparable to the regenerative effects obtained with SC transplantation [ 9 , 10 , 11 ]. At the same time, the clinical use of stem cells themselves is still associated with problems resulting primarily from their low survival rate after transplantation [ 12 , 13 ].…”