Temporal perturbation of the Wnt signaling pathway in the control of cell reprogramming is modulated by TCF1

• Published in: Stem cell reports 2014-05, Vol.2 (5), p.707-720
• Main Authors: Aulicino, Francesco, Theka, Ilda, Ombrato, Luigi, Lluis, Frederic, Cosma, Maria Pia
• Format: Article
• Language: English
• Subjects: Animals; Antibiotics, Antineoplastic - pharmacology; beta Catenin - genetics; beta Catenin - metabolism; Cell Line; Cellular Reprogramming - drug effects; Doxorubicin - pharmacology; Epithelial-Mesenchymal Transition; Hepatocyte Nuclear Factor 1-alpha - antagonists & inhibitors; Hepatocyte Nuclear Factor 1-alpha - genetics; Hepatocyte Nuclear Factor 1-alpha - metabolism; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; Induced Pluripotent Stem Cells - cytology; Induced Pluripotent Stem Cells - metabolism; Mice; RNA Interference; RNA, Small Interfering - metabolism; Transcription Factors - genetics; Transcription Factors - metabolism; Wnt Proteins - genetics; Wnt Proteins - metabolism; Wnt Signaling Pathway
• ISSN: 2213-6711; 2213-6711
• DOI: 10.1016/j.stemcr.2014.04.001

Cyclic activation of the Wnt/β-catenin signaling pathway controls cell fusion-mediated somatic cell reprogramming. TCFs belong to a family of transcription factors that, in complex with β-catenin, bind and transcriptionally regulate Wnt target genes. Here, we show that Wnt/β-catenin signaling needs to be off during the early reprogramming phases of mouse embryonic fibroblasts (MEFs) into iPSCs. In MEFs undergoing reprogramming, senescence genes are repressed and mesenchymal-to-epithelial transition is favored. This is correlated with a repressive activity of TCF1, which contributes to the silencing of Wnt/β-catenin signaling at the onset of reprogramming. In contrast, the Wnt pathway needs to be active in the late reprogramming phases to achieve successful reprogramming. In conclusion, continued activation or inhibition of the Wnt/β-catenin signaling pathway is detrimental to the reprogramming of MEFs; instead, temporal perturbation of the pathway is essential for efficient reprogramming, and the "Wnt-off" state can be considered an early reprogramming marker.