title: Valproic Acid Enhances iPSC Induction From Human Bone Marrow-Derived Cells Through the Suppression of Reprogramming-Induced Senescence.
abstract: Reprogramming of human somatic cells into pluripotent cells (iPSCs) by defined transcription factors is an extremely inefficient process. Treatment with the histone deacetylase inhibitor valproic acid (VPA) during reprogramming can improve the induction of iPSCs. To examine the specific mechanism underlying the role of VPA in reprogramming, we transfected human bone marrow-derived cells (HSC-J2 and HSC-L1) with lentiviruses carrying defined factors (OCT4, SOX2, KLF4, and c-MYC, OSKM) in the presence of VPA. We found that, OSKM lentiviruses caused significant senescence in transfected cells. Administration of VPA, however, significantly suppressed this reprogramming-induced stress. Notably, VPA treatment improved cell proliferation in the early stages of reprogramming, and this was related to the down-regulation of the activated p16/p21 pathway. In addition, VPA also released the G2/M phase blockade in lentivirus-transfected cells. This study demonstrates a new mechanistic role of the histone deacetylase inhibitor in enhancing the induction of pluripotency. J. Cell. Physiol. 231: 1719-1727, 2016. © 2015 Wiley Periodicals, Inc.
authors.affiliation: Stem Cell and Cancer Center, First Affiliated Hospital, Jilin University, Changchun, Jilin, P.R. China.|Stanford University Medical School, Palo Alto Veterans Institute for Research, Palo Alto, California.
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.affiliation: Stem Cell and Cancer Center, First Affiliated Hospital, Jilin University, Changchun, Jilin, P.R. China.|Stanford University Medical School, Palo Alto Veterans Institute for Research, Palo Alto, California.
authors.forename: Yingying
authors.initials: Y
authors.lastname: Zhai
authors.affiliation: Stem Cell and Cancer Center, First Affiliated Hospital, Jilin University, Changchun, Jilin, P.R. China.|Stanford University Medical School, Palo Alto Veterans Institute for Research, Palo Alto, California.
authors.forename: Dehai
authors.initials: D
authors.lastname: Yu
authors.affiliation: Stem Cell and Cancer Center, First Affiliated Hospital, Jilin University, Changchun, Jilin, P.R. China.
authors.forename: Jiuwei
authors.initials: J
authors.lastname: Cui
authors.affiliation: Stem Cell and Cancer Center, First Affiliated Hospital, Jilin University, Changchun, Jilin, P.R. China.|Stanford University Medical School, Palo Alto Veterans Institute for Research, Palo Alto, California.
authors.forename: Ji-Fan
authors.initials: JF
authors.lastname: Hu
authors.affiliation: Stem Cell and Cancer Center, First Affiliated Hospital, Jilin University, Changchun, Jilin, P.R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
mesh_terms: D001854:Bone Marrow Cells / Q000187:drug effects* / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D065150:Cellular Reprogramming / Q000187:drug effects*; D016922:Cellular Senescence / Q000187:drug effects*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D005822:Genetic Vectors; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000187:drug effects* / Q000378:metabolism; D000090062:Kruppel-Like Factor 4; D016086:Lentivirus / Q000235:genetics; D010641:Phenotype; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D014635:Valproic Acid / Q000494:pharmacology*
chemical_list: C493956:CDKN1A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D056572:Histone Deacetylase Inhibitors; C000715467:KLF4 protein, human; D000090062:Kruppel-Like Factor 4; D014157:Transcription Factors; D014635:Valproic Acid