Small extracellular vesicles from mesenchymal stem cells: A potential Weapon for chronic non-healing wound treatment

Abstract

Chronic non-healing wounds have posed a severe threat to patients mentally and physically. Behavior dysregulation of remaining cells at wound sites is recognized as the chief culprit to destroy healing process and hinders wound healing. Therefore, regulating and restoring normal cellular behavior is the core of chronic non-healing wound treatment. In recent years, the therapy with mesenchymal stem cells (MSCs) has become a promising option for chronic wound healing and the efficacy has increasingly been attributed to their exocrine functions. Small extracellular vesicles derived from MSCs (MSC-sEVs) are reported to benefit almost all stages of wound healing by regulating the cellular behavior to participate in the process of inflammatory response, angiogenesis, re-epithelization, and scarless healing. Here, we describe the characteristics of MSC-sEVs and discuss their therapeutic potential in chronic wound treatment. Additionally, we also provide an overview of the application avenues of MSC-sEVs in wound treatment. Finally, we summarize strategies for large-scale production and engineering of MSC-sEVs. This review may possibly provide meaningful guidance for chronic wound treatment with MSC-sEVs.

Keywords: cell dysfunction; chronic non-healing wounds; mesenchymal stem cells; regenerative medicine; small extracellular vesicles.

FIGURE 1

Comparison of representative pathophysiological processes between normal healing wounds and chronic non-healing wounds. Normal wound healing process can be divided into four distinct and overlapping phases: hemostasis, inflammation, proliferation, and remodeling (A). However, chronic wounds usually halt at inflammation phase and are difficult to heal because of excessive inflammation, senescent skin cells, poor vascularization, and increased matrix metalloproteinases (B).

FIGURE 2

The content of MSC-sEVs and extensive sources of MSCs. The isolated sEVs from MSCs are enriched in a large variety of therapeutic molecules. The sources of MSCs are extensive including bone marrow, umbilical cord, placenta, adipose tissue, synovial membrane, exfoliated deciduous teeth, menstrual blood, and induced pluripotent stem cells (iPSCs).

FIGURE 3

MSC-sEVs promote wound healing process by multiple mechanisms. MSC-sEVs can regulate inflammatory response by inhibiting proliferation of immune cells and shifting polarization of macrophages (i). MSC-sEVs stimulate angiogenesis by promoting VEGF-mediated migration and proliferation of endothelial cells (ii). MSC-sEVs boost re-epithelization by inhibiting SASPs and apoptosis and increasing the viability and migration of keratinocytes (iii). MSC-sEVs inhibit scar formation by modulating transformation of fibroblasts to myofibroblasts (iv).

FIGURE 4

Application avenues of sEVs including injection of free sEVs and combination with advanced biomaterials. Free sEVs are applied by means of local injection or intravenous injection (A). MSC-sEVs are loaded in hydrogel pads, microneedle array, microspheres, and electrospun fibers (B).