title: Activation of p38, p21, and NRF-2 mediates decreased proliferation of human dental pulp stem cells cultured under 21% O2.
abstract: High rates of stem cell proliferation are important in regenerative medicine and in stem cell banking for clinical use. Ambient oxygen tensions (21% O2) are normally used for in vitro culture, but physiological levels in vivo range between 3% and 6% O2. We compared proliferation of human dental pulp stem cells (hDPSCs) cultured under 21% versus 3% O2. The rate of hDPSC proliferation is significantly lower at 21% O2 compared to physiological oxygen levels due to enhanced oxidative stress. Under 21% O2, increased p38 phosphorylation led to activation of p21. Increased generation of reactive oxygen species and p21 led to activation of the NRF-2 signaling pathway. The upregulation of NRF-2 antioxidant defense genes under 21% O2 may interact with cell-cycle-related proteins involved in regulating cell proliferation. Activation of p38/p21/NRF-2 in hDPSCs cultured under ambient oxygen tension inhibits stem cell proliferation and upregulates NRF-2 antioxidant defenses.
authors.affiliation: Department of Physiology, Faculty of Medicine, University of Valencia, 46010 Valencia, Spain.
authors.forename: Marya
authors.initials: M
authors.lastname: El Alami
authors.affiliation: Department of Odontology, Faculty of Medicine, University of Valencia, 46010 Valencia, Spain.
authors.forename: Jose
authors.initials: J
authors.lastname: Viña-Almunia
authors.affiliation: Department of Physiology, Faculty of Medicine, University of Valencia, 46010 Valencia, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Gambini
authors.affiliation: Department of Physiology, Faculty of Medicine, University of Valencia, 46010 Valencia, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Mas-Bargues
authors.affiliation: Cardiovascular Division, British Heart Foundation Centre of Research Excellence, School of Medicine, King's College London, London SE1 9NH, UK.
authors.forename: Richard C M
authors.initials: RC
authors.lastname: Siow
authors.affiliation: Department of Odontology, Faculty of Medicine, University of Valencia, 46010 Valencia, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Peñarrocha
authors.affiliation: Cardiovascular Division, British Heart Foundation Centre of Research Excellence, School of Medicine, King's College London, London SE1 9NH, UK.
authors.forename: Giovanni E
authors.initials: GE
authors.lastname: Mann
authors.affiliation: Department of Physiology, Faculty of Medicine, University of Valencia, 46010 Valencia, Spain.
authors.forename: Consuelo
authors.initials: C
authors.lastname: Borrás
authors.affiliation: Department of Physiology, Faculty of Medicine, University of Valencia, 46010 Valencia, Spain. Electronic address: jose.vina@uv.es.
authors.forename: Jose
authors.initials: J
authors.lastname: Viña
mesh_terms: D000293:Adolescent; D053687:Adult Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D049109:Cell Proliferation; D002478:Cells, Cultured; D003782:Dental Pulp / Q000166:cytology*; D006801:Humans; D008297:Male; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress; D010100:Oxygen / Q000494:pharmacology; D055815:Young Adult; D054462:p21-Activated Kinases / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D054462:p21-Activated Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D010100:Oxygen