Transient Expression of WNT2 Promotes Somatic Cell Reprogramming by Inducing β-Catenin Nuclear Accumulation

摘要

class="head no_bottom_margin" id="sec1title">IntroductionSomatic cells can be reprogrammed to induced pluripotent stem cells (iPSCs) by ectopic expression of defined transcription factors (OCT3/4, KLF4, SOX2, and c-MYC, hereafter referred to as OKSM) (). While the changes in gene expressions and epigenetic modifications during reprogramming have been well studied (, , , , , ), the changes in activities of signaling pathways have not been extensively studied.The Wnt signaling pathway controls the pluripotency of embryonic stem cells (ESCs) (). Wnt ligands inhibit GSK3 activity, resulting in β-catenin stabilization. Stabilized β-catenin then translocates into the nucleus and regulates gene expression. Mouse ESCs secrete Wnt ligands, and the autocrine Wnt activity is required for the maintenance of pluripotency (). Mouse ESCs can even be maintained in the so-called 2i culture condition, the GSK3 inhibitor plus the MEK inhibitor (). While Wnt/β-catenin signaling activates self-renewal of ESCs, it also plays a critical role in the initiation of differentiation (), suggesting its divergent role in ESCs.The role of Wnt/β-catenin signaling in reprogramming has also been investigated. Exogenously introduced WNT3A enhances fibroblast reprogramming in the absence of c-Myc (). Knockdown or knockout of T cell factors or treatments with several drugs that control the Wnt pathway can change the reprogramming efficiency (, , , href="#bib27" rid="bib27" class=" bibr popnode">Ross et al., 2014, href="#bib36" rid="bib36" class=" bibr popnode">Zhang et al., 2014). However, it remains controversial whether endogenous Wnt/β-catenin signaling has a stimulatory or inhibitory effect on reprogramming. Furthermore, the dynamics and role of endogenous Wnt ligands or β-catenin in reprogramming remain largely unanswered.In this study, we find that transient upregulation of WNT2 induces β-catenin nuclear accumulation and promotes cellular reprogramming.