Extracellular Vesicles in Musculoskeletal Regeneration: Modulating the Therapy of the Future

Abstract

Tissue regeneration is a hot topic in health sciences, particularly because effective therapies promoting the healing of several cell types are lacking, specifically those of the musculoskeletal system. Mesenchymal Stem/Stromal Cells (MSCs) have been identified as crucial players in bone homeostasis, and are considered a promising therapy for diseases such as osteoarthritis (OA) and Rheumatoid Arthritis (RA). However, some known drawbacks limit their use, particularly ethical issues and immunological rejections. Thus, MSCs byproducts, namely Extracellular Vesicles (EVs), are emerging as potential solutions to overcome some of the issues of the original cells. EVs can be modulated by either cellular preconditioning or vesicle engineering, and thus represent a plastic tool to be implemented in regenerative medicine. Further, the use of biomaterials is important to improve EV delivery and indirectly to modulate their content and secretion. This review aims to connect the dots among MSCs, EVs, and biomaterials, in the context of musculoskeletal diseases.

Keywords: biomaterials; extracellular vesicles; mesenchymal stem/stromal cells; regenerative medicine.

Figure 1

Cell-to-cell Communication via EVs in the Musculoskeletal System. (A) MSCs can be found in the bone marrow, adipose tissue, dental pulp, peripheral blood, umbilical cord, and among other tissues. (B) MSCs release EVs containing proteins, lipids, and nucleic acids (DNA and miRNA) to the surrounding environment. EVs can be formed either through plasma membrane budding (microvesicles) or through an endosomal route (exosomes). (C) They express surface markers that interact with the membrane receptors of the target cells (chondrocytes, myocytes, osteoclasts, osteoblasts, immune cells, tenocytes, among others) impacting the vesicle uptake and cargo delivery or directly stimulating and/or reprogramming the target cell. Created with BioRender.com.

Figure 2

Engineering EVs and Their Applications. Cell preconditioning/engineering may increase the production and secretion of EVs, while also modulating its content in a controlled manner. These vesicles can then be delivered in combination with scaffold/biomaterials to ensure correct targeting, by conferring protection to the EVs and allowing a controlled release of their content. Thus, this strategy can lead to an improvement in tissue regeneration, through stimulation of several cell processes including proliferation, calcification and differentiation. The images depicting EVs production and release were obtained by Transmission Electron Microscopy (TEM); PLA and tissue regeneration images were obtained by the ground sections method in brightfield imaging; hydrogel, collagen and ceramics images were obtained by Scanning Electron Microscopy (SEM); the image representing proliferation was captured by confocal microscopy; the Alizarin Red staining used to detect calcification was captured in brightfield microscopy. All images belong to the authors.