Mesenchymal stem cell secreted vesicles provide novel opportunities in (stem) cell-free therapy

Abstract

Mesenchymal stem cells (MSCs) are adult multipotent cells that give rise to various cell types of the mesodermal germ layer. MSCs are of great interest in the field of regenerative medicine and cancer therapy because of their unique ability to home to damaged and cancerous tissue. These cells also regulate the immune response and contribute to reparative processes in different pathological conditions, including musculoskeletal and cardiovascular diseases. The use of MSCs for tissue repair was initially based on the hypothesis that these cells home to and differentiate within the injured tissue into specialized cells. However, it now appears that only a small proportion of transplanted MSCs actually integrate and survive in host tissues. Thus, the predominant mechanism by which MSCs participate in tissue repair seems to be related to their paracrine activity. Indeed, MSCs provide the microenvironment with a multitude of trophic and survival signals including growth factors and cytokines. Recent discoveries suggest that lipid microvesicles released by MSCs may also be important in the physiological function of these cells. Over the past few years the biological relevance of micro- and nano-vesicles released by cells in intercellular communication has been established. Alongside the conventional mediators of cell secretome, these sophisticated nanovesicles transfer proteins, lipids and, most importantly, various forms of RNAs to neighboring cells, thereby mediating a variety of biological responses. The physiological role of MSC-derived vesicles (MSC-MVs) is currently not well understood. Nevertheless, encouraging results indicate that MSC-MVs have similar protective and reparative properties as their cellular counterparts in tissue repair and possibly anti-cancer therapy. Thus, MSC-MVs represent a promising opportunity to develop novel cell-free therapy approaches that might overcome the obstacles and risks associated with the use of native or engineered stem cells.

Keywords: exosomes; mesenchymal stem cell (MSC); microvesicles; regenerative medicine; therapy.

Figure 1

Mesenchymal stem cell properties and relevance for therapeutic applications. Mesenchymal stem cells (MSCs) can be isolated from different sources, in particular from bone marrow and adipose tissues, and can differentiate into various cell types of the mesodermal germ layer. The possibility that these adult stem cells can differentiate in cells of the other germ layers is not excluded and is still debated. Two main properties make MSCs good candidates for therapeutic applications. First, their ability to enter the blood circulation and home to sites of inflammation, i.e., damaged and cancerous tissues, where MSCs can release a multitude of trophic factors. Second, MSCs have the ability to suppress the immune system via different mechanism. While the latter property, together with the tropism for injured sites, can be exploited in the field of regenerative medicine, the homing of MSCs, engineered to carry anti-proliferative or pro-apoptotic signals, to cancer may be important for the development of anticancer therapy approaches.

Figure 2

Schematic representation of exosome biogenesis. Intraluminal vesicles (ILVs) are generated by the inward budding of the limiting membrane of a subgroup of late endosomes called multivesicular bodies (MVBs). MVBs can be directed towards the cell periphery and, after fusion with the plasma membrane, release their content in the extracellular space. Secreted ILVs, now called “exosomes,” are then taken up by target cells (A). Electron microscopy picture of exosomes isolated by differential ultracentrifugation (B).

Figure 3

Proposed model for therapeutic applications of MSC-derived exosomes. MSC-derived exosomes may be used instead of MSCs in regenerative medicine and anticancer therapy, since they seem to hold the beneficial properties of the parental cells. MSC-derived exosomes might retain the homing ability displayed by MSCs towards sites of inflammation and function in tissue repair, also by modulating the immune response. Concerning anticancer therapy, exosomes derived from engineered MSCs might be used to mediate anti-proliferative or pro-apoptotic effects. Moreover, whenever the tropism of exosomes would not be retained, MSCs may be modified to confer specific targeting to exosomes.