Histone deacetylase inhibitor valproic acid promotes the induction of pluripotency in mouse fibroblasts by suppressing reprogramming-induced senescence stress

Journal Article · Thu Sep 10 04:00:00 EDT 2015 · Experimental Cell Research

DOI:https://doi.org/10.1016/J.YEXCR.2015.06.003· OSTI ID:22462326

Zhai, Yingying; Chen, Xi; Yu, Dehai ^[1]; Li, Tao ^[2]; Cui, Jiuwei; Wang, Guanjun ^[1]; Hu, Ji-Fan ^[1]; Li, Wei ^[1]

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1. Stem Cell and Cancer Center, First Affiliated Hospital, Jilin University, Changchun, Jilin 130061 (China)
2. Stanford University Medical School, Palo Alto Veterans Institute for Research, Palo Alto, CA 94304 (United States)

Histone deacetylase inhibitor valproic acid (VPA) has been used to increase the reprogramming efficiency of induced pluripotent stem cell (iPSC) from somatic cells, yet the specific molecular mechanisms underlying this effect is unknown. Here, we demonstrate that reprogramming with lentiviruses carrying the iPSC-inducing factors (Oct4-Sox2-Klf4-cMyc, OSKM) caused senescence in mouse fibroblasts, establishing a stress barrier for cell reprogramming. Administration of VPA protected cells from reprogramming-induced senescent stress. Using an in vitro pre-mature senescence model, we found that VPA treatment increased cell proliferation and inhibited apoptosis through the suppression of the p16/p21 pathway. In addition, VPA also inhibited the G2/M phase blockage derived from the senescence stress. These findings highlight the role of VPA in breaking the cell senescence barrier required for the induction of pluripotency. - Highlights: • Histone deacetylase inhibitor valproic acid enhances iPSC induction. • Valproic acid suppresses reprogramming-induced senescence stress. • Valproic acid downregulates the p16/p21 pathway in reprogramming. • This study demonstrates a new mechanistic role of valproic acid in enhancing reprogramming.

• OSTI ID: 22462326
• Journal Information: Experimental Cell Research, Journal Name: Experimental Cell Research Journal Issue: 1 Vol. 337; ISSN 0014-4827; ISSN ECREAL
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
APOPTOSIS
CELL CYCLE
CELL PROLIFERATION
DIFFUSION BARRIERS
EFFICIENCY
FIBROBLASTS
IN VITRO
INDUCTION
INHIBITION
MANAGEMENT
MICE
MONOCLINIC LATTICES
PHOSPHORUS 21
STEM CELLS
STRESSES
VENTILATION BARRIERS