Wnt/β-Catenin/TCF Pathway Is a Phase-Dependent Promoter of Colony Formation and Mesendodermal Differentiation During Human Somatic Cell Reprogramming.

Somatic cell reprogramming is a biphasic phenomenon that goes through a mesenchymal-to-epithelial transition, called initiation phase, followed by a maturation phase wherein reprogramming cells acquire pluripotency. Here, we show that these phases display a differential response to Wnt signaling activation. Wnt signaling increases colony formation by promoting cellular epithelialization during the initiation phase in a TCF7-dependent manner. However, during maturation phase, it is also responsible for inducing mesendodermal differentiation, which is negatively regulated by TCF7L1. Thus, Wnt signaling inhibition or TCF7L1 overexpression downregulates mesendodermal gene expression without perturbing pluripotency. Together, our results demonstrate that a phase-specific modulation of Wnt signaling leads to an improved reprogramming efficiency in terms of colony output and pluripotency acquisition. This work provides new insights into the cell context-dependent roles of Wnt signaling during human somatic cell reprogramming. Stem Cells 2018;36:683-695.