NANOG priming before full reprogramming may generate germ cell tumours
1 Department of Obstetrics and Gynaecology, Geneva University Hospitals, Geneva, Switzerland
2 Section of Dental Medicine, University of Geneva, Geneva, Switzerland
3 Department of Pathology and Immunology, University of Geneva Medical School, Geneva, Switzerland
4 CNS Research Department, Hoffmann-LaRoche, Basel, Switzerland
5 Division of Obstetrics and Gynaecology, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Huddinge, Sweden
6 Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland
7 Institute of Oral Biology, Faculty of Medicine, University of Zurich, Zurich, Switzerland
8 Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden
§ These authors contributed equally to the paper
§§ These authors contributed equally to the paper
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 tumoursin 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.
Keywords
- Induced pluripotent stem cells
- stem cells
- cancer stem cells
- NANOG
- cancer
- germ-cell tumour
- reprogramming
- pluripotency
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