Extracellular Vesicles from Mesenchymal Stem Cells as Novel Treatments for Musculoskeletal Diseases

Abstract

Mesenchymal stem/stromal cells (MSCs) represent a promising therapy for musculoskeletal diseases. There is compelling evidence indicating that MSC effects are mainly mediated by paracrine mechanisms and in particular by the secretion of extracellular vesicles (EVs). Many studies have thus suggested that EVs may be an alternative to cell therapy with MSCs in tissue repair. In this review, we summarize the current understanding of MSC EVs actions in preclinical studies of (1) immune regulation and rheumatoid arthritis, (2) bone repair and bone diseases, (3) cartilage repair and osteoarthritis, (4) intervertebral disk degeneration and (5) skeletal muscle and tendon repair. We also discuss the mechanisms underlying these actions and the perspectives of MSC EVs-based strategies for future treatments of musculoskeletal disorders.

Keywords: bone diseases; extracellular vesicles; immunoregulation; mesenchymal stem cells; osteoarthritis..

Figure 1

Examples of immunomodulatory effects exerted by mesenchymal stem/stromal cell extracellular vesicles (MSC EVs). EVs inhibit the production of pro-inflammatory cytokines but increase the levels of anti-inflammatory cytokines in monocytic cells. They exert negative effects on dendritic cell maturation and activation with impairment of antigen uptake and also on the proliferation of CD4⁺ T cells, CD8⁺ T cells, NK cells and B cells. These EVs promote the conversion of Th1 into Th2 and reduce Th17 differentiation. In contrast, MSC EVs enhance the differentiation of regulatory cells such as M2 macrophages, CD4⁺CD25⁺FOXP3⁺Treg and CD4⁺IL-10⁺Tr1.

Figure 2

Effects of MSC EVs on bone repair and bone diseases. MSC EVs enhance proliferation, migration and osteogenic differentiation of BM-MSCs whereas apoptosis is inhibited. In addition, proliferation and recruitment of endothelial cells/endothelial progenitor are promoted leading to angiogenesis. MSC EVs also reduce osteoclast formation and osteocyte-like cells apoptosis.

Figure 3

Effects of MSC EVs on cartilage repair and osteoarthritis (OA). In chondrocytes, MSC EVs downregulate pro-inflammatory mediators such as IL-1β, IL-6, IL-8, IL-17, CCL-2, CCL-5, NO and PGE₂ as well as catabolic enzymes MMPs and ADAMTS5. Besides, these EVs enhance chondrocyte proliferation, autophagy and the synthesis of cartilage extracellular matrix. IL-10 levels are increased in OA chondrocytes and subchondral osteoblasts. In these last cells, MSC EVs also exert anti-inflammatory effects and reduce mitochondrial membrane alterations and oxidative stress to protect osteoblasts from stress-induced senescence.