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Review
. 2022 Feb 7;23(3):1865.
doi: 10.3390/ijms23031865.

Educating EVs to Improve Bone Regeneration: Getting Closer to the Clinic

Arantza Infante  1 , Natividad Alcorta-Sevillano  1   2 , Iratxe Macías  1 , Clara I Rodríguez  1
Affiliations
Review

Educating EVs to Improve Bone Regeneration: Getting Closer to the Clinic

Arantza Infante et al. Int J Mol Sci. .

Abstract

The incidence of bone-related disorders is continuously growing as the aging of the population in developing countries continues to increase. Although therapeutic interventions for bone regeneration exist, their effectiveness is questioned, especially under certain circumstances, such as critical size defects. This gap of curative options has led to the search for new and more effective therapeutic approaches for bone regeneration; among them, the possibility of using extracellular vesicles (EVs) is gaining ground. EVs are secreted, biocompatible, nano-sized vesicles that play a pivotal role as messengers between donor and target cells, mediated by their specific cargo. Evidence shows that bone-relevant cells secrete osteoanabolic EVs, whose functionality can be further improved by several strategies. This, together with the low immunogenicity of EVs and their storage advantages, make them attractive candidates for clinical prospects in bone regeneration. However, before EVs reach clinical translation, a number of concerns should be addressed. Unraveling the EVs' mode of action in bone regeneration is one of them; the molecular mediators driving their osteoanabolic effects in acceptor cells are now beginning to be uncovered. Increasing the functional and bone targeting abilities of EVs are also matters of intense research. Here, we summarize the cell sources offering osteoanabolic EVs, and the current knowledge about the molecular cargos that mediate bone regeneration. Moreover, we discuss strategies under development to improve the osteoanabolic and bone-targeting potential of EVs.

Keywords: MSCs; bone regeneration; extracellular vesicles; miRNAs; osteoanabolic.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Illustration of the bone-relevant cell types known to secrete EVs that promote bone regeneration. Pro-osteogenic and pro-angiogenic EVs, determined by their specific cargo, are produced by cell types present in bone microenvironment, such as mesenchymal stem cells (MSCs), osteoblasts, osteocytes, macrophages, and endothelial cells (ECs). Pro-osteogenic EVs stimulate MSCs and osteoblasts differentiation, inducing the bone formation process, while pro-angiogenic EVs elicit the formation of new blood vessels in bone tissue. Both processes are essential to conduct a successful regeneration of bone tissue. The figure was created with BioRender.com (accessed on 1 December 2021).
Figure 2
Figure 2
Preconditioning strategies to enhance the osteoanabolic potential of EVs. Pre-treatment of MSCs with inflammatory factors or histone deacetylase inhibitors enhance their osteogenic differentiation, whereas hypoxia conditions elicit pro-angiogenic responses in these cells, leading to the secretion of pro-osteogenic or pro-angiogenic EVs, respectively. Mechanistically, the mimicking of the bone inflammatory microenvironment after bone injury triggers the expression of the pro-osteogenic protein WNT3a in MSCs, which in turn, is enriched in the EVs secreted by these cells. The inhibition of histone deacetylases, such as via the use of thrichostatin A (TSA), elicits an epigenetic reprogramming of MSCs, ensuring an open conformation of chromatin and promoting the transcription of pro-osteogenic genes. The hypoxia simulation in MSCs, achieved by low oxygen cell culture or by chemical compounds (for instance dimethyloxaylglycine (DMOG)), induces the activation of the HIF-1α transcription factor, which drives the cell responses to hypoxia, among them being hypoxia-induced angiogenesis. The figure was created with BioRender.com (accessed on 1 December 2021).
Figure 3
Figure 3
Genetic engineering as an approach to enrich EVs with osteoanabolic factors. The induced expression of known osteoanabolic miRNAs, proteins, or inhibitors of anti-osteogenic miRNAs in MSCs, by using expression vectors or direct transfection approaches of these molecules, yields EVs enriched in these molecules. The figure was created with BioRender.com (accessed on 1 December 2021).
Figure 4
Figure 4
Functionalization of EVs’ surface to improve bone targeting. The surface modification of EVs with molecules showing affinity for bone cells has been described. This is the case of specific aptamers, DNA/RNA molecules with affinity for a desired target, and in this case MSCs and osteoblasts. Anti-resorptive drugs, such as bisphosphonates (BPs), which show high affinity for the mineralized bone matrix, have also been covalently bound to the surface of EVs. Both approaches have demonstrated increased bone targeting of functionalized EVs. The figure was created with BioRender.com (accessed on 1 December 2021).
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