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World J Stem Cells. Feb 26, 2017; 9(2): 26-36
Published online Feb 26, 2017. doi: 10.4252/wjsc.v9.i2.26
Regulation of mitochondrial function and endoplasmic reticulum stress by nitric oxide in pluripotent stem cells
Estefania Caballano-Infantes, José Terron-Bautista, Amparo Beltrán-Povea, Gladys M Cahuana, Bernat Soria, Hajji Nabil, Francisco J Bedoya, Juan R Tejedo
Estefania Caballano-Infantes, José Terron-Bautista, Amparo Beltrán-Povea, Gladys M Cahuana, Francisco J Bedoya, Juan R Tejedo, Andalusian Center for Molecular Biology and Regenerative Medicine-University Pablo de Olavide, 41092 Seville, Spain
Gladys M Cahuana, Bernat Soria, Francisco J Bedoya, Juan R Tejedo, Biomedical Research Network on Diabetes and Related Metabolic Diseases (CIBERDEM), Instituto de Salud Carlos III, 28029 Madrid, Spain
Bernat Soria, Francisco J Bedoya, Juan R Tejedo, Andalusian Center for Molecular Biology and Regenerative Medicine (CABIMER), 41092 Seville, Spain
Bernat Soria, Andalusian Center for Molecular Biology and Regenerative Medicine, Fundación Progreso y Salud, 41092 Seville, Spain
Hajji Nabil, Centre for Pharmacology and Therapeutics, Division of Experimental Medicine, Imperial College London, Hammersmith Hospital Campus, London W12 0NN, United Kingdom
Author contributions: All the authors contributed to this manuscript.
Supported by Ministerio de Ciencia E Innovación - Bernat Soria - Innpacto Proyect, No. IPT-2011-1615-900000; Instituto de Salud Carlos III, Gobierno de España - Bernat Soria, No. TERCEL RD06/0010/0025; Consejeria de Salud Junta de Andalucia - Francisco Javier Bedoya Bergua, No. PI-0105-2010; Consejeria de Economia Innovación Ciencia y Empleo - Junta de Andalucia - Francisco Javier Bedoya, No. CTS-7127/2011.
Conflict-of-interest statement: None.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (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: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Juan R Tejedo, PhD, Andalusian Center for Molecular Biology and Regenerative Medicine-University Pablo de Olavide, Parque Científico y Tecnológico Cartuja 93, 41092 Seville, Spain. juan.tejedo@cabimer.es
Telephone: +34-954-467840 Fax: +34-954-461664
Received: June 14, 2016
Peer-review started: June 17, 2016
First decision: July 27, 2016
Revised: September 9, 2016
Accepted: January 11, 2017
Article in press: January 14, 2017
Published online: February 26, 2017
Processing time: 255 Days and 8.6 Hours
Abstract

Mitochondrial dysfunction and endoplasmic reticulum stress (ERS) are global processes that are interrelated and regulated by several stress factors. Nitric oxide (NO) is a multifunctional biomolecule with many varieties of physiological and pathological functions, such as the regulation of cytochrome c inhibition and activation of the immune response, ERS and DNA damage; these actions are dose-dependent. It has been reported that in embryonic stem cells, NO has a dual role, controlling differentiation, survival and pluripotency, but the molecular mechanisms by which it modulates these functions are not yet known. Low levels of NO maintain pluripotency and induce mitochondrial biogenesis. It is well established that NO disrupts the mitochondrial respiratory chain and causes changes in mitochondrial Ca2+ flux that induce ERS. Thus, at high concentrations, NO becomes a potential differentiation agent due to the relationship between ERS and the unfolded protein response in many differentiated cell lines. Nevertheless, many studies have demonstrated the need for physiological levels of NO for a proper ERS response. In this review, we stress the importance of the relationships between NO levels, ERS and mitochondrial dysfunction that control stem cell fate as a new approach to possible cell therapy strategies.

Keywords: Endoplasmic reticulum stress; Mitochondrial function; Nitric oxide; Pluripotency; Cell differentiation; Mitochondrial biogenesis

Core tip: Several studies have focused on the role of nitric oxide (NO) in regulating many physiological functions, such as metabolism and pluripotency. NO has been established to act as a potent agent for the control of stemness by promoting the expansion of pluripotent cells. NO regulates mitochondrial function and endoplasmic reticulum stress. In pluripotent stem cells, both of these factors are related to the control of cell fate and may contribute to the mechanism by which NO regulates the maintenance of pluripotency. This provides additional evidence supporting the use of NO as an alternative small molecule for the conservation and expansion of cultured pluripotent cell lines necessary for implementing a cell therapy programme.