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 O 2 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.

Mesenchymal stem cell‐derived extracellular vesicles in treatment against renal fibrosis

“…Various methods have emerged such as 3D cultures, bioreactors, physical and electrical stimulation, chemical induction of EV-secreting cells and others. 37,[92][93][94] Currently, large-scale and efficient production of MSC-EVs is still unattainable. Therefore, further investigation of more advanced production technology is needed.…”

“…Third, large amounts of MSC‐EVs are required to satisfy clinical treatment; however, MSC‐EVs have a rather short half‐life and are difficult to preserve, although more and more researchers have focused on the methods of scalable productions of EVs and achieved some exciting results. Various methods have emerged such as 3D cultures, bioreactors, physical and electrical stimulation, chemical induction of EV‐secreting cells and others 37,92–94 . Currently, large‐scale and efficient production of MSC‐EVs is still unattainable.…”

“…Preconditioning under different culture conditions enhances the effectiveness of MSC‐EVs. Pulido‐Escribano et al found that MSC‐EVs prepared under hypoxic conditions have higher regenerative capacity than those under normoxic conditions 94 . Yu et al.…”

Use of Brain-Derived Stem/Progenitor Cells and Derived Extracellular Vesicles to Repair Damaged Neural Tissues: Lessons Learned from Connective Tissue Repair Regarding Variables Limiting Progress and Approaches to Overcome Limitations

“…As an alternative to using NSC/NPC, it is possible to appropriately differentiated stromal/stem cells isolated from other environment alone (i.e., MSC) or in combination with NSC [ 83 ], induced pluripotent stem cells (iPSC) derived from an appropriate somatic cell [ 84 , 85 , 86 , 87 ], or extracellular vesicles (EV) derived from MSC or a relevant cell cultured under optimal in vitro culture conditions [ 88 , 89 ]. The latter are becoming an important avenue of research as they are not immunogenetic, can contain a range of molecules that can enhance endogenous cell repair of the damaged tissue, and could therefore be used in non-autologous application, which would overcome potential limitations associated with autologous materials.…”

“…The potential of EV to facilitate repair in acute neurological conditions and in chronic conditions have been reviewed recently by a number of authors [ 94 , 95 , 96 , 97 ]. As their effectiveness depends in part on their content, the ability to influence their content by altering the in vitro conditions they are generated from also provides flexibility in their application [ 88 , 89 ]. Furthermore, the use of allogenic EV would also overcome concerns regarding EV derived from the brain of patients with neurodegenerative conditions [ 98 ].…”