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World J Stem Cells. Jul 26, 2022; 14(7): 453-472
Published online Jul 26, 2022. doi: 10.4252/wjsc.v14.i7.453
Role of hypoxia preconditioning in therapeutic potential of mesenchymal stem-cell-derived extracellular vesicles
Victoria Pulido-Escribano, Bárbara Torrecillas-Baena, Marta Camacho-Cardenosa, Gabriel Dorado, María Ángeles Gálvez-Moreno, Antonio Casado-Díaz
Victoria Pulido-Escribano, Bárbara Torrecillas-Baena, Marta Camacho-Cardenosa, María Ángeles Gálvez-Moreno, Antonio Casado-Díaz, Unidad de Gestión Clínica de Endocrinología y Nutrición-GC17, Instituto Maimónides de Investigación Biomédica de Córdoba, Hospital Universitario Reina Sofía, Córdoba 14004, Spain
Gabriel Dorado, Dep. Bioquímica y Biología Molecular, Campus Rabanales C6-1-E17, Campus de Excelencia Internacional Agroalimentario (ceiA3), Universidad de Córdoba, CIBERFES, Córdoba 14071, Spain
Author contributions: Pulido-Escribano V, Torrecillas-Baena B, and Casado-Díaz A designed the study; Pulido-Escribano V, Torrecillas-Baena B, Camacho-Cardenosa M, and Casado-Díaz A conducted reviews and literature analyses; Dorado G, Gálvez-Moreno MÁ, and Casado-Díaz A drafted and edited; all authors reviewed and approved the final version.
Supported by “Instituto de Salud Carlos III” (ISCIII), “Ministerio de Economía y Competitividad” (MINECO) and European Union (EU), No. PI18/01659 and No. PI21/01935.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Antonio Casado-Díaz, PhD, Research Scientist, Unidad de Gestión Clínica de Endocrinología y Nutrición-GC17, Instituto Maimónides de Investigación Biomédica de Córdoba, Hospital Universitario Reina Sofía, Avda, Menéndez Pidal, s/n, Córdoba 14004, Spain. bb1cadia@uco.es
Received: March 17, 2022
Peer-review started: March 17, 2022
First decision: April 18, 2022
Revised: May 2, 2022
Accepted: July 11, 2022
Article in press: July 11, 2022
Published online: July 26, 2022
Processing time: 130 Days and 15.7 Hours
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.