Stage-Specific Regulation of Reprogramming to Induced Pluripotent Stem Cells by Wnt Signaling and T Cell Factor Proteins
Ritchie Ho,
Bernadett Papp,
Jackson A. Hoffman,
Bradley J. Merrill,
Kathrin Plath
Affiliations
Ritchie Ho
Department of Biological Chemistry, Jonsson Comprehensive Cancer Center, Molecular Biology Institute, Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, David Geffen School of Medicine, University of California Los Angeles, 615 Charles E. Young Drive South, Los Angeles, CA 90024, USA
Bernadett Papp
Department of Biological Chemistry, Jonsson Comprehensive Cancer Center, Molecular Biology Institute, Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, David Geffen School of Medicine, University of California Los Angeles, 615 Charles E. Young Drive South, Los Angeles, CA 90024, USA
Jackson A. Hoffman
Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, IL 60607, USA
Bradley J. Merrill
Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, IL 60607, USA
Kathrin Plath
Department of Biological Chemistry, Jonsson Comprehensive Cancer Center, Molecular Biology Institute, Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, David Geffen School of Medicine, University of California Los Angeles, 615 Charles E. Young Drive South, Los Angeles, CA 90024, USA
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.
