Journal
CELL REPORTS
Volume 3, Issue 6, Pages 2113-2126Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2013.05.015
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Funding
- NIH [DP2OD001686, P01 GM099134, 5T32AI060567-07, R01-CA128571]
- CIRM [RN1-00564]
- UCLA Broad Center of Regenerative Medicine and Stem Cell Research
- UCLA Graduate Division Dissertation Year Fellowship
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Wnt signaling is intrinsic to mouse embryonic stem cell self-renewal. Therefore, it is surprising that reprogramming of somatic cells to induced pluripotent stem cells (iPSCs) is not strongly enhanced by Wnt signaling. Here, we demonstrate that active Wnt signaling inhibits the early stage of reprogramming to iPSCs, whereas it is required and even stimulating during the late stage. Mechanistically, this biphasic effect of Wnt signaling is accompanied by a change in the requirement of all four of its transcriptional effectors: T cell factor 1 (Tcf1), Lef1, Tcf3, and Tcf4. For example, Tcf3 and Tcf4 are stimulatory early but inhibitory late in the reprogramming process. Accordingly, ectopic expression of Tcf3 early in reprogramming combined with its loss of function late enables efficient reprogramming in the absence of ectopic Sox2. Together, our data indicate that the stepwise process of reprogramming to iPSCs is critically dependent on the stage-specific control and action of all four Tcfs and Wnt signaling.
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