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

Figure 1 Hypoxia-inducible factor 1A protein regulation in hypoxia. Hypoxia-inducible factor (HIF) 1A is continuously hydroxylated and degraded by the proteosome, when O₂ concentrations are greater than 5%. However, in hypoxia (O₂ < 5%) HIF1A hydroxylation is inhibited and it accumulates in the cytoplasm. It then translocates to the nucleus, where it forms a heterodimer with HIF1B. This, together with the coactivator CBP/P300, binds to hypoxic-response elements at gene-promoter sites, activating transcription of genes involved in biological processes such as angiogenesis, proliferation, migration, inflammatory response, metabolism, and apoptosis, among others. This produces physiological adaptive responses of cells to hypoxia. HIF: Hypoxia-inducible factor; HRE: Hypoxic-response elements; PHD: Prolyl HyDroxylases; VHL: Von Hippel-Lindau.

Figure 2 Clinical potential of extracellular vesicles from preconditioned mesenchymal stem-cells under hypoxia. Mesenchymal stem-cell (MSC) exposed to hypoxia secrete extracellular vesicles (EV) that can be isolated and used for clinical purposes, such as treatment of wound healing and bone fractures, as well as cardiovascular, neurodegenerative, and renal diseases, among others. Isolation of EV is made from MSC culture medium, which can be carried out in different ways. In this case, the use of a size-exclusion column is shown. EV secreted under hypoxia were enriched in various proteins, nucleic acids (like microRNA), as well as grow factors that are implicated in modulation and improvement of different biological processes related to tissue regeneration in different pathologies. EV: Extracellular vesicles; MSC: Mesenchymal stem-cell.