Role of p16INK4a and BMI-1 in oxidative stress-induced premature senescence in human dental pulp stem cells
Cristina Mas-Bargues,
José Viña-Almunia,
Marta Inglés,
Jorge Sanz-Ros,
Juan Gambini,
José Santiago Ibáñez-Cabellos,
José Luis García-Giménez,
José Viña,
Consuelo Borrás
Affiliations
Cristina Mas-Bargues
Department of Physiology. Faculty of Medicine and Dentistry. University of Valencia, Av/ Blasco Ibáñez, 15, 46010 Valencia, Spain; INCLIVA Health Research Institute, Av/ de Menéndez y Pelayo, 4, 46010 Valencia, Spain; Center for Biomedical Network Research on Frailty and Healthy Aging (CIBERFES), CIBER-ISCIII, Spain
José Viña-Almunia
Department of Stomatology. Faculty of Medicine and Dentistry. University of Valencia, Av/ Blasco Ibáñez, 15, 46010 Valencia, Spain
Marta Inglés
Department of Physiotherapy. Faculty of Medicine and Dentistry. University of Valencia, Av/ Blasco Ibáñez, 15, 46010 Valencia, Spain; INCLIVA Health Research Institute, Av/ de Menéndez y Pelayo, 4, 46010 Valencia, Spain; Center for Biomedical Network Research on Frailty and Healthy Aging (CIBERFES), CIBER-ISCIII, Spain
Jorge Sanz-Ros
Department of Physiology. Faculty of Medicine and Dentistry. University of Valencia, Av/ Blasco Ibáñez, 15, 46010 Valencia, Spain; INCLIVA Health Research Institute, Av/ de Menéndez y Pelayo, 4, 46010 Valencia, Spain; Center for Biomedical Network Research on Frailty and Healthy Aging (CIBERFES), CIBER-ISCIII, Spain
Juan Gambini
Department of Physiology. Faculty of Medicine and Dentistry. University of Valencia, Av/ Blasco Ibáñez, 15, 46010 Valencia, Spain; INCLIVA Health Research Institute, Av/ de Menéndez y Pelayo, 4, 46010 Valencia, Spain; Center for Biomedical Network Research on Frailty and Healthy Aging (CIBERFES), CIBER-ISCIII, Spain
José Santiago Ibáñez-Cabellos
Department of Physiology. Faculty of Medicine and Dentistry. University of Valencia, Av/ Blasco Ibáñez, 15, 46010 Valencia, Spain; Center for Biomedical Network Research on Rare Diseases (CIBERER), CIBER-ISCIII, Spain; INCLIVA Health Research Institute, Av/ de Menéndez y Pelayo, 4, 46010 Valencia, Spain
José Luis García-Giménez
Department of Physiology. Faculty of Medicine and Dentistry. University of Valencia, Av/ Blasco Ibáñez, 15, 46010 Valencia, Spain; Center for Biomedical Network Research on Rare Diseases (CIBERER), CIBER-ISCIII, Spain; INCLIVA Health Research Institute, Av/ de Menéndez y Pelayo, 4, 46010 Valencia, Spain
José Viña
Department of Physiology. Faculty of Medicine and Dentistry. University of Valencia, Av/ Blasco Ibáñez, 15, 46010 Valencia, Spain; INCLIVA Health Research Institute, Av/ de Menéndez y Pelayo, 4, 46010 Valencia, Spain; Center for Biomedical Network Research on Frailty and Healthy Aging (CIBERFES), CIBER-ISCIII, Spain
Consuelo Borrás
Department of Physiology. Faculty of Medicine and Dentistry. University of Valencia, Av/ Blasco Ibáñez, 15, 46010 Valencia, Spain; INCLIVA Health Research Institute, Av/ de Menéndez y Pelayo, 4, 46010 Valencia, Spain; Center for Biomedical Network Research on Frailty and Healthy Aging (CIBERFES), CIBER-ISCIII, Spain; Corresponding author at: Department of Physiology, Faculty of Medicine, Avenida Blasco Ibañez 15, 46010 Valencia, Spain.
Human dental pulp stem cells (hDPSCs) are a source for cell therapy. Before implantation, an in vitro expansion step is necessary, with the inconvenience that hDPSCs undergo senescence following a certain number of passages, loosing their stemness properties. Long-term in vitro culture of hDPSCs at 21% (ambient oxygen tension) compared with 3–6% oxygen tension (physiological oxygen tension) caused an oxidative stress-related premature senescence, as evidenced by increased β-galactosidase activity and increased lysil oxidase expression, which is mediated by p16INK4a pathway. Furthermore, hDPSCs cultured at 21% oxygen tension underwent a downregulation of OCT4, SOX2, KLF4 and c-MYC factors, which was recued by BMI-1 silencing. Thus, p16INK4a and BMI-1 might play a role in the oxidative stress-associated premature senescence. We show that it is important for clinical applications to culture cells at physiological pO2 to retain their stemness characteristics and to delay senescence. Keywords: Oxygen tension, Regenerative medicine, Aging
