iPSCs can be generated from somatic cells through the expression of four transcription factors, Oct3/4 (also known as Pou5f1), SRY-box 2 (Sox2), Krüppel-like factor 4 (Klf4) and Myc (OSKM). Using a chimeric mouse model in which expression of the four transcription factors was induced by doxycycline (OSKM mice), the authors found that induction of the four factors for 4 weeks generated teratomas in multiple tissues, which indicated that somatic cell reprogramming had occurred in vivo. However, if the four factors were induced for 3–7 days, dysplasia occurred in multiple epithelial tissues, but these dysplastic lesions were no longer detectable after withdrawal of doxycycline. Labelling of the dysplastic cells showed that they became integrated into epithelial tissues and appeared to be normal on doxycycline withdrawal. This indicates that OSKM-mediated somatic cell reprogramming for less than 7 days results in transient cellular changes that lead to reversible dysplasia. However, when the four factors were induced for more than 7 days (after which doxycycline was withdrawn) the mice developed epithelial-derived tumours that were not teratomas, which indicates that these cells have undergone partial reprogramming. Furthermore, tumour cells derived from kidney tumours that formed in these mice produced tumours on transplantation into immunocompromised mice, thereby confirming that these cells have undergone irreversible neoplastic changes.
Next, the authors sought to characterize the epithelial tumours induced by the four factors in OSKM mice. Focusing on kidney tumours, they found that the tumour cells had lost their kidney cell identity and shared some characteristics with pluripotent stem cells and embryonic stem cells (ESCs). Importantly, in contrast to ESCs, OSKM-induced kidney tumour cells exhibited expression of polycomb repressive complex (PRC) target genes, which indicates that a failure to induce PRC-mediated repression causes partial reprogramming and tumorigenesis. The authors also found that OSKM-induced kidney tumour cells had gained ESC-associated DNA methylation patterns. There was also similarity between gene expression in OSKM-induced kidney tumours and Wilms' tumour (a paediatric kidney cancer). However, OSKM-induced kidney tumour cells did not have any evidence of genetic abnormalities, which indicates that epigenetic alteration drives tumorigenesis in this model.
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