title: NANOG priming before full reprogramming may generate germ cell tumours.
abstract: Reprogramming somatic cells into a pluripotent state brings patient-tailored, ethical controversy-free cellular therapy closer to reality. However, stem cells and cancer cells share many common characteristics; therefore, it is crucial to be able to discriminate between them. We generated two induced pluripotent stem cell (iPSC) lines, with NANOG pre-transduction followed by OCT3/4, SOX2, and LIN28 overexpression. One of the cell lines, CHiPS W, showed normal pluripotent stem cell characteristics, while the other, CHiPS A, though expressing pluripotency markers, failed to differentiate and gave rise to germ cell-like tumours in vivo. Comparative genomic hybridisation analysis of the generated iPS lines revealed that they were genetically more stable than human embryonic stem cell counterparts. This analysis proved to be predictive for the differentiation potential of analysed cells. Moreover, the CHiPS A line expressed a lower ratio of p53/p21 when compared to CHiPS W. NANOG pre-induction followed by OCT3/4, SOX2, MYC, and KLF4 induction resulted in the same tumour-inducing phenotype. These results underline the importance of a re-examination of the role of NANOG during reprogramming. Moreover, this reprogramming method may provide insights into primordial cell tumour formation and cancer stem cell transformation.
authors.affiliation: Department of Obstetrics and Gynaecology, Geneva University Hospitals, Geneva, Switzerland.
authors.forename: I
authors.initials: I
authors.lastname: Grad
authors.forename: Y
authors.initials: Y
authors.lastname: Hibaoui
authors.forename: M
authors.initials: M
authors.lastname: Jaconi
authors.forename: L
authors.initials: L
authors.lastname: Chicha
authors.forename: R
authors.initials: R
authors.lastname: Bergström-Tengzelius
authors.forename: M R
authors.initials: MR
authors.lastname: Sailani
authors.forename: M F
authors.initials: MF
authors.lastname: Pelte
authors.forename: S
authors.initials: S
authors.lastname: Dahoun
authors.forename: T A
authors.initials: TA
authors.lastname: Mitsiadis
authors.forename: V
authors.initials: V
authors.lastname: Töhönen
authors.forename: S
authors.initials: S
authors.lastname: Bouillaguet
authors.forename: S E
authors.initials: SE
authors.lastname: Antonarakis
authors.forename: J
authors.initials: J
authors.lastname: Kere
authors.forename: M
authors.initials: M
authors.lastname: Zucchelli
authors.forename: O
authors.initials: O
authors.lastname: Hovatta
authors.forename: A
authors.initials: A
authors.lastname: Feki
mesh_terms: D000818:Animals; D001483:Base Sequence; D002454:Cell Differentiation; D002460:Cell Line; D065150:Cellular Reprogramming; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism; D059785:Karyotype; D000090062:Kruppel-Like Factor 4; D051379:Mice; D016513:Mice, SCID; D000071317:Nanog Homeobox Protein; D009373:Neoplasms, Germ Cell and Embryonal / Q000209:etiology* / Q000473:pathology; D050814:Octamer Transcription Factor-3 / Q000096:biosynthesis / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000096:biosynthesis; D055748:SOXB1 Transcription Factors / Q000096:biosynthesis; D017423:Sequence Analysis, RNA
chemical_list: D018398:Homeodomain Proteins; C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; C000715187:Lin28A protein, human; C486780:NANOG protein, human; D000071317:Nanog Homeobox Protein; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; D016601:RNA-Binding Proteins; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors