title: Histone deacetylase inhibitor valproic acid promotes the induction of pluripotency in mouse fibroblasts by suppressing reprogramming-induced senescence stress.
abstract: 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.
authors.affiliation: Stem Cell and Cancer Center, First Affiliated Hospital, Jilin University, Changchun, Jilin 130061, PR China; Stanford University Medical School, Palo Alto Veterans Institute for Research, Palo Alto, CA 94304, USA.
authors.forename: Yingying
authors.initials: Y
authors.lastname: Zhai
authors.affiliation: Stem Cell and Cancer Center, First Affiliated Hospital, Jilin University, Changchun, Jilin 130061, PR China; Stanford University Medical School, Palo Alto Veterans Institute for Research, Palo Alto, CA 94304, USA.
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.affiliation: Stem Cell and Cancer Center, First Affiliated Hospital, Jilin University, Changchun, Jilin 130061, PR China; Stanford University Medical School, Palo Alto Veterans Institute for Research, Palo Alto, CA 94304, USA.
authors.forename: Dehai
authors.initials: D
authors.lastname: Yu
authors.affiliation: Stanford University Medical School, Palo Alto Veterans Institute for Research, Palo Alto, CA 94304, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Li
authors.affiliation: Stem Cell and Cancer Center, First Affiliated Hospital, Jilin University, Changchun, Jilin 130061, PR China.
authors.forename: Jiuwei
authors.initials: J
authors.lastname: Cui
authors.affiliation: Stem Cell and Cancer Center, First Affiliated Hospital, Jilin University, Changchun, Jilin 130061, PR China.
authors.forename: Guanjun
authors.initials: G
authors.lastname: Wang
authors.affiliation: Stem Cell and Cancer Center, First Affiliated Hospital, Jilin University, Changchun, Jilin 130061, PR China; Stanford University Medical School, Palo Alto Veterans Institute for Research, Palo Alto, CA 94304, USA. Electronic address: jifan@stanford.edu.
authors.forename: Ji-Fan
authors.initials: JF
authors.lastname: Hu
authors.affiliation: Stem Cell and Cancer Center, First Affiliated Hospital, Jilin University, Changchun, Jilin 130061, PR China. Electronic address: jdyylw@163.com.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation; D065150:Cellular Reprogramming; D016922:Cellular Senescence; D005347:Fibroblasts / Q000187:drug effects* / Q000502:physiology; D059565:G2 Phase Cell Cycle Checkpoints; D015870:Gene Expression / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D057026:Induced Pluripotent Stem Cells / Q000502:physiology*; D000090062:Kruppel-Like Factor 4; D051379:Mice; D008807:Mice, Inbred BALB C; D014635:Valproic Acid / Q000494:pharmacology*
chemical_list: D018797:Cell Cycle Proteins; D056572:Histone Deacetylase Inhibitors; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D014635:Valproic Acid
keywords: Cell cycle; Pluripotency; Senescence; Stem cell; Valproic acid; iPSC; p16; p21