Extracellular Vesicles Derived From Mesenchymal Stem Cells (MSC) in Regenerative Medicine: Applications in Skin Wound Healing

Abstract

The cells secrete extracellular vesicles (EV) that may have an endosomal origin, or from evaginations of the plasma membrane. The former are usually called exosomes, with sizes ranging from 50 to 100 nm. These EV contain a lipid bilayer associated to membrane proteins. Molecules such as nucleic acids (DNA, mRNA, miRNA, lncRNA, etc.) and proteins may be stored inside. The EV composition depends on the producer cell type and its physiological conditions. Through them, the cells modify their microenvironment and the behavior of neighboring cells. That is accomplished by transferring factors that modulate different metabolic and signaling pathways. Due to their properties, EV can be applied as a diagnostic and therapeutic tool in medicine. The mesenchymal stromal cells (MSC) have immunomodulatory properties and a high regenerative capacity. These features are linked to their paracrine activity and EV secretion. Therefore, research on exosomes produced by MSC has been intensified for use in cell-free regenerative medicine. In this area, the use of EV for the treatment of chronic skin ulcers (CSU) has been proposed. Such sores occur when normal healing does not resolve properly. That is usually due to excessive prolongation of the inflammatory phase. These ulcers are associated with aging and diseases, such as diabetes, so their prevalence is increasing with the one of such latter disease, mainly in developed countries. This has very important socio-economic repercussions. In this review, we show that the application of MSC-derived EV for the treatment of CSU has positive effects, including accelerating healing and decreasing scar formation. This is because the EV have immunosuppressive and immunomodulatory properties. Likewise, they have the ability to activate the angiogenesis, proliferation, migration, and differentiation of the main cell types involved in skin regeneration. They include endothelial cells, fibroblasts, and keratinocytes. Most of the studies carried out so far are preclinical. Therefore, there is a need to advance more in the knowledge about the conditions of production, isolation, and action mechanisms of EV. Interestingly, their potential application in the treatment of CSU opens the door for the design of new highly effective therapeutic strategies.

Exosomes derived from atorvastatin-pretreated MSC accelerate diabetic wound repair by enhancing angiogenesis via AKT/eNOS pathway

“…By transporting nutrients, oxygen, and growth factors to the injury sites, the formation of new blood vessels is essential for skin tissue regeneration during the wound healing [ 10 ]. However, the dysfunction of endothelial cells in diabetes contributes to the decline in angiogenesis, characterized by decreased vascularity and capillary density.…”

Mesenchymal stromal cell therapies: immunomodulatory properties and clinical progress

“…In comparison to whole cell-based therapies, MSC-EV-related therapeutics promotes concept of cell-free "cell therapy 2.0" [237], given EV exhibiting specific advantages for patient safety such as lower propensity to trigger innate and adaptive immune responses and inability to directly form tumors. Nonetheless, various important questions regarding EV standardization, MoA underlining EV transmitted biological information in the form of proteins, glycoproteins, lipids and ribonucleic acids, and costeffective production must be methodically addressed [236][237][238][239][240].…”

Clinical Translational Potential in Skin Wound Regeneration for Adipose-Derived, Blood-Derived, and Cellulose Materials: Cells, Exosomes, and Hydrogels

“…These proteins can be secreted directly into the medium or are endocytosed and enclosed within extracellular vesicles such as exosomes. The exosomes are membrane-bound microvesicles that are characteristically enclosed by membranes containing tetraspanin proteins (CD9, CD63, CD81), lysosomal-associated membrane proteins (LAMP1/2), and tumor susceptibility gene 101 (TSG101) as hallmarks [ 54 , 55 ]. Exosome or extracellular vesicles derived from human ASCs have been used to accelerate the healing of full-thickness skin wounds in rodent models [ 54 , 56 ].…”

“…The exosomes are membrane-bound microvesicles that are characteristically enclosed by membranes containing tetraspanin proteins (CD9, CD63, CD81), lysosomal-associated membrane proteins (LAMP1/2), and tumor susceptibility gene 101 (TSG101) as hallmarks [ 54 , 55 ]. Exosome or extracellular vesicles derived from human ASCs have been used to accelerate the healing of full-thickness skin wounds in rodent models [ 54 , 56 ]. Following injection into the wound, the ASC extracellular vesicles activated the AKT and ERK pathways to improve closure, collagen deposition, and vascularization [ 56 ].…”

“…The ASC-derived microRNAs are capable of modulating wound healing by driving lineage differentiation along the adipocyte, chondrocyte, myocyte, and osteoblast pathways [ 57 ]. Additionally, it is hypothesized that exosomal microRNAs similarly modulate pathways involved in the inflammatory, proliferative, angiogenic, and remodeling phases of wound healing [ 54 ]. A number of methods are used to isolate and concentrate exosomes, including differential centrifugation, ultra-centrifugation, size exclusion chromatography, immunoselection, and precipitation [ 55 ].…”