Role of hypoxia preconditioning in therapeutic potential of mesenchymal stem-cell-derived extracellular vesicles

Abstract

The use of mesenchymal stem-cells (MSC) in cell therapy has received considerable attention because of their properties. These properties include high expansion and differentiation in vitro, low immunogenicity, and modulation of biological processes, such as inflammation, angiogenesis and hematopoiesis. Curiously, the regenerative effect of MSC is partly due to their paracrine activity. This has prompted numerous studies, to investigate the therapeutic potential of their secretome in general, and specifically their extracellular vesicles (EV). The latter contain proteins, lipids, nucleic acids, and other metabolites, which can cause physiological changes when released into recipient cells. Interestingly, contents of EV can be modulated by preconditioning MSC under different culture conditions. Among them, exposure to hypoxia stands out; these cells respond by activating hypoxia-inducible factor (HIF) at low O₂ concentrations. HIF has direct and indirect pleiotropic effects, modulating expression of hundreds of genes involved in processes such as inflammation, migration, proliferation, differentiation, angiogenesis, metabolism, and cell apoptosis. Expression of these genes is reflected in the contents of secreted EV. Interestingly, numerous studies show that MSC-derived EV conditioned under hypoxia have a higher regenerative capacity than those obtained under normoxia. In this review, we show the implications of hypoxia responses in relation to tissue regeneration. In addition, hypoxia preconditioning of MSC is being evaluated as a very attractive strategy for isolation of EV, with a high potential for clinical use in regenerative medicine that can be applied to different pathologies.

Keywords: Cell priming, Extracellular vesicles, Hypoxia, Hypoxia-inducible factor, Mesenchymal stem-cells, Regenerative medicine

Core Tip: Mesenchymal stem-cells (MSC)-derived EV have a high therapeutic interest. The composition of extracellular vesicles (EV) depends on the state of source cells, generating physiological changes in recipient cells. MSC culture preconditioning affects the cargos of EV. Thus, hypoxia exposition leads to hypoxia-inducible factor induction and regulation of hundreds of genes involved in processes such as inflammation, migration, proliferation, differentiation, angiogenesis, metabolism, and apoptosis. This affects the contents of secreted EV. Accordingly, numerous studies have shown that EV from MSC under hypoxia have a higher regenerative capacity than those obtained under normoxia. Therefore, the former have a high clinical potential in different pathologies.