title: The homeobox gene DLX4 promotes generation of human induced pluripotent stem cells.
abstract: The reprogramming of somatic cells into induced pluripotent stem cells (iPSCs) by defined transcription factors has been a well-established technique and will provide an invaluable resource for regenerative medicine. However, the low reprogramming efficiency of human iPSC is still a limitation for clinical application. Here we showed that the reprogramming potential of human dental pulp cells (DPCs) obtained from immature teeth is much higher than those of mature teeth DPCs. Furthermore, immature teeth DPCs can be reprogrammed by OCT3/4 and SOX2, conversely these two factors are insufficient to convert mature teeth DPCs to pluripotent states. Using a gene expression profiles between these two DPC groups, we identified a new transcript factor, distal-less homeobox 4 (DLX4), which was highly expressed in immature teeth DPCs and significantly promoted human iPSC generation in combination with OCT3/4, SOX2, and KLF4. We further show that activation of TGF-β signaling suppresses the expression of DLX4 in DPCs and impairs the iPSC generation of DPCs. Our findings indicate that DLX4 can functionally replace c-MYC and supports efficient reprogramming of immature teeth DPCs.
authors.affiliation: Department of Oral and Maxillofacial Science, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu City, Gifu 501-1194, Japan.
authors.forename: Naritaka
authors.initials: N
authors.lastname: Tamaoki
authors.affiliation: Center for iPS Cell Research and Application, Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Kazutoshi
authors.initials: K
authors.lastname: Takahashi
authors.affiliation: Department of Tissue and Organ Development, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu City, Gifu 501-1194, Japan.
authors.forename: Hitomi
authors.initials: H
authors.lastname: Aoki
authors.affiliation: Department of Oral and Maxillofacial Science, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu City, Gifu 501-1194, Japan.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Iida
authors.affiliation: Department of Oral and Maxillofacial Science, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu City, Gifu 501-1194, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Kawaguchi
authors.affiliation: Department of Oral and Maxillofacial Science, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu City, Gifu 501-1194, Japan.
authors.forename: Daijirou
authors.initials: D
authors.lastname: Hatakeyama
authors.affiliation: Laboratory of Medical Therapeutics and Molecular Therapeutics, Gifu Pharmaceutical University, 1-25-4 Daigaku-Nishi, Gifu 501-1195, Japan.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Inden
authors.affiliation: Division of Cellular Biosignal Sciences, Department of Biochemistry, Iwate Medical University, 19-1 Uchimaru, Morioka, Iwate 020-8505, Japan.
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Chosa
authors.affiliation: Division of Cellular Biosignal Sciences, Department of Biochemistry, Iwate Medical University, 19-1 Uchimaru, Morioka, Iwate 020-8505, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Ishisaki
authors.affiliation: Department of Tissue and Organ Development, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu City, Gifu 501-1194, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Kunisada
authors.affiliation: Department of Oral and Maxillofacial Science, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu City, Gifu 501-1194, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Shibata
authors.affiliation: Molecular Profiling Research Center for Drug Discovery, National Institute of Advanced Industrial Science and Technology, 2-4-7 Aomi, Koto-ku, Tokyo 135-0064, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Goshima
authors.affiliation: Center for iPS Cell Research and Application, Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Yamanaka
authors.affiliation: Department of Tissue and Organ Development, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu City, Gifu 501-1194, Japan.
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Tezuka
mesh_terms: D002478:Cells, Cultured; D065150:Cellular Reprogramming / Q000235:genetics; D005801:Genes, Homeobox / Q000235:genetics*; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000502:physiology*; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics; D050814:Octamer Transcription Factor-3 / Q000235:genetics; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D055748:SOXB1 Transcription Factors / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics*; D059467:Transcriptome / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000235:genetics
chemical_list: C105304:DLX4 protein, human; D018398:Homeodomain Proteins; C000715467:KLF4 protein, human; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; D016271:Proto-Oncogene Proteins c-myc; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; D014157:Transcription Factors; D016212:Transforming Growth Factor beta