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.

Keywords: exosomes; extracellular vesicles; mesenchymal stem cells; regenerative medicine; skin; wound healing.

FIGURE 1

Types of extracellular vesicles. They are classified taking into account their origin. Thus, they include the ones derived from endosomes (exosomes), evagination of the plasma membrane (microvesicles), and vesicles from apoptosis (apoptotic vesicles). The lower part shows the exosome structure, including its main cargo molecules.

FIGURE 2

Endosomal biogenesis of exosomes. The endosomes generate multi-vesicular bodies. The latter carry different types of molecules, like RNA and proteins. Such cargos are partially added in a specific way. The MVB may be degraded by the lysosomes, or merge with the plasma membrane, dumping contents to the extracellular space. The exosomes may bind and activate different membrane receptors in the target cells. Alternatively, they can be engulfed, releasing their cargos into the cell. The exosomes may modulate numerous physiological process, though such mechanisms.

FIGURE 3

Applications of extracellular vesicles in medicine. The EV obtained from cellular cultures may be applied to patients with specific therapeutic objectives. For instance, the ones derived from cells with regenerative capacity (like MSC) may be used for tissue regeneration. Additionally, the producing cells may be bioengineered to produce EV enriched in some cellular molecules (like specific RNA or proteins), or being loaded with specific drugs. This way, the EV work as vehicles for efficiently targeting the delivery of such molecules to patients. On the other hand, the exosomes can also be isolated from different fluids or tissues of healthy persons, as well as patients suffering different diseases. That allows to identify biomarkers in them, for subsequent diagnostic applications.

FIGURE 4

Timeline of skin wound healing. The different phases are shown. The most relevant processes for each stage, as well as their overlapping with others, are graphically and quantitatively depicted for each step.

FIGURE 5

Effects of MSC extracellular vesicles on wound healing. Graphical abstract of the current state-of-the-art knowledge of the EV actions on skin wound healing. The effects on different cell types involved in such a physiological process are shown. They include immune and endothelial cells, fibroblasts, and keratinocytes.