Clinical Potential of Mesenchymal Stem Cell-Derived Exosomes in Bone Regeneration

Abstract

Bone metabolism is regulated by osteoblasts, osteoclasts, osteocytes, and stem cells. Pathologies such as osteoporosis, osteoarthritis, osteonecrosis, and traumatic fractures require effective treatments that favor bone formation and regeneration. Among these, cell therapy based on mesenchymal stem cells (MSC) has been proposed. MSC are osteoprogenitors, but their regenerative activity depends in part on their paracrine properties. These are mainly mediated by extracellular vesicle (EV) secretion. EV modulates regenerative processes such as inflammation, angiogenesis, cell proliferation, migration, and differentiation. Thus, MSC-EV are currently an important tool for the development of cell-free therapies in regenerative medicine. This review describes the current knowledge of the effects of MSC-EV in the different phases of bone regeneration. MSC-EV has been used by intravenous injection, directly or in combination with different types of biomaterials, in preclinical models of bone diseases. They have shown great clinical potential in regenerative medicine applied to bone. These findings should be confirmed through standardization of protocols, a better understanding of the mechanisms of action, and appropriate clinical trials. All that will allow the translation of such cell-free therapy to human clinic applications.

Keywords: biomaterials; bone; cell-free therapy; exosomes; extracellular vesicles; mesenchymal stem cells; regenerative medicine.

Figure 1

Bone regeneration phases. (1) Hematoma formation: infiltration of neutrophils, macrophages, and lymphocytes. (2) Fibrocartilage callus formation: recruitment of fibroblasts and mesenchymal stem cells. The last one differentiates into chondrocytes at the fracture site. (3) Bony callus formation: differentiation of chondroblasts, chondroclasts, osteoblasts, and osteoclasts is stimulated. Then, cartilaginous calluses are resorbed and begin to calcify. (4) Bone remodeling: osteoblasts and osteoclasts will give rise to successive cycles of remodeling to produce mature bone tissues.

Figure 2

Effects of MSC-EV on bone regeneration. MSC-EV have the capacity to modulate different processes related to bone formation and regeneration. They include inflammation, angiogenesis, differentiation, and cell migration. This is due to their cargos, which have high (↑) or low (↓) levels of different molecules with biological activity (growth factors, cytokines, miRNA, lncRNA, etc.). They intervene in the induction or inhibition of different signaling pathways related to these processes. To stimulate secretion of EV with high regenerative capacity in MSC cultures, cells can be preconditioned with different molecules [TNFα, PTH 1-34, tauroursodeoxycholic acid (TUDCA), and dimethyloxalylglycine (DMOG)], nanoparticles (Fe₃O₄ NP), bioactive glass nanoparticles (BGN), or culture conditions (osteoblast differentiation and hypoxia). MSC-EV can be applied for the treatment of bone defects, incorporating them into biomaterials that serve as vehicles and delivery systems for them. Thus, cell migration, proliferation, and differentiation are facilitated in the scaffolds, enabling bone regeneration. Hydrogels, porous scaffolds, and those resulting from the combination of both are interesting biomaterials with great potential for treating bone damage.