Stemness of Human Pluripotent Cells: Hypoxia-Like Response Induced by Low Nitric Oxide
Estefanía Caballano-Infantes,
Irene Díaz,
Ana Belén Hitos,
Gladys Margot Cahuana,
Antonio Martínez-Ruiz,
Bárbara Soria-Juan,
Rosario Rodríguez-Griñolo,
Abdelkrim Hmadcha,
Franz Martín,
Bernat Soria,
Juan R. Tejedo,
Francisco Javier Bedoya
Affiliations
Estefanía Caballano-Infantes
Department of Regeneration and Cell Therapy, Andalusian Center for Molecular Biology and Regenerative Medicine (CABIMER), University of Pablo de Olavide-University of Seville-CSIC, 41013 Seville, Spain
Irene Díaz
Department of Regeneration and Cell Therapy, Andalusian Center for Molecular Biology and Regenerative Medicine (CABIMER), University of Pablo de Olavide-University of Seville-CSIC, 41013 Seville, Spain
Ana Belén Hitos
Department of Regeneration and Cell Therapy, Andalusian Center for Molecular Biology and Regenerative Medicine (CABIMER), University of Pablo de Olavide-University of Seville-CSIC, 41013 Seville, Spain
Gladys Margot Cahuana
Department of Molecular Biology and Biochemical Engineering, Universidad Pablo de Olavide, 41013 Seville, Spain
Antonio Martínez-Ruiz
Unidad de Investigación, Hospital Universitario Santa Cristina, Instituto de Investigación Sanitaria Princesa (IIS-IP), E-28009 Madrid, Spain
Bárbara Soria-Juan
Fundación Jiménez Díaz Health Research Institute, 28040 Madrid, Spain
Rosario Rodríguez-Griñolo
Departamento de Economía, Métodos Cuantitativo e Historia Económica, Universidad Pablo de Olavide, 41013 Seville, Spain
Abdelkrim Hmadcha
Department of Regeneration and Cell Therapy, Andalusian Center for Molecular Biology and Regenerative Medicine (CABIMER), University of Pablo de Olavide-University of Seville-CSIC, 41013 Seville, Spain
Franz Martín
Department of Regeneration and Cell Therapy, Andalusian Center for Molecular Biology and Regenerative Medicine (CABIMER), University of Pablo de Olavide-University of Seville-CSIC, 41013 Seville, Spain
Bernat Soria
Biomedical Research Network for Diabetes and Related Metabolic Diseases-CIBERDEM, Instituto de Salud Carlos III, 08036 Madrid, Spain
Juan R. Tejedo
Department of Regeneration and Cell Therapy, Andalusian Center for Molecular Biology and Regenerative Medicine (CABIMER), University of Pablo de Olavide-University of Seville-CSIC, 41013 Seville, Spain
Francisco Javier Bedoya
Department of Regeneration and Cell Therapy, Andalusian Center for Molecular Biology and Regenerative Medicine (CABIMER), University of Pablo de Olavide-University of Seville-CSIC, 41013 Seville, Spain
The optimization of conditions to promote the stemness of pluripotent cells in vitro is instrumental for their use in advanced therapies. We show here that exposure of human iPSCs and human ESCs to low concentrations of the chemical NO donor DETA/NO leads to stabilization of hypoxia-inducible factors (HIF-1α and HIF-2α) under normoxia, with this effect being dependent on diminished Pro 402 hydroxylation and decreased degradation by the proteasome. Moreover, the master genes of pluripotency, NANOG and OCT-4, were upregulated. NO also induces a shift in the metabolic profile of PSCs, with an increased expression of hypoxia response genes in glycolysis. Furthermore, a reduction in the mitochondrial membrane potential with lower oxygen consumption and increased expression of mitochondrial fusion regulators, such as DRP1, was observed. The results reported here indicate that NO mimics hypoxia response in human PSCs and enhances their stemness properties when cultured under normoxic conditions.
