Marucci Lucia, Pedone Elisa, Di Vicino Umberto, Sanuy-Escribano Blanca, Isalan Mark, Cosma Maria Pia
Centre for Genomic Regulation (CRG), 08003 Barcelona, Spain; Department of Engineering Mathematics, University of Bristol, Bristol BS8 1UB, UK.
Centre for Genomic Regulation (CRG), 08003 Barcelona, Spain.
Cell Rep. 2014 Sep 25;8(6):1686-1696. doi: 10.1016/j.celrep.2014.08.011. Epub 2014 Sep 4.
The Wnt/β-catenin pathway and Nanog are key regulators of embryonic stem cell (ESC) pluripotency and the reprogramming of somatic cells. Here, we demonstrate that the repression of Dkk1 by Nanog, which leads indirectly to β-catenin activation, is essential for reprogramming after fusion of ESCs overexpressing Nanog. In addition, β-catenin is necessary in Nanog-dependent conversion of preinduced pluripotent stem cells (pre-iPSCs) into iPSCs. The activation of β-catenin by Nanog causes fluctuations of β-catenin in ESCs cultured in serum plus leukemia inhibitory factor (serum+LIF) medium, in which protein levels of key pluripotency factors are heterogeneous. In 2i+LIF medium, which favors propagation of ESCs in a ground state of pluripotency with many pluripotency genes losing mosaic expression, we show Nanog-independent β-catenin fluctuations. Overall, we demonstrate Nanog and β-catenin cooperation in establishing naive pluripotency during the reprogramming process and their correlated heterogeneity in ESCs primed toward differentiation.
Wnt/β-连环蛋白信号通路和Nanog是胚胎干细胞（ESC）多能性及体细胞重编程的关键调节因子。在此，我们证明Nanog对Dkk1的抑制作用（间接导致β-连环蛋白激活）对于过表达Nanog的ESC融合后的重编程至关重要。此外，β-连环蛋白在Nanog依赖的预诱导多能干细胞（pre-iPSC）向iPSC的转化过程中是必需的。Nanog对β-连环蛋白的激活导致在添加血清和白血病抑制因子（血清+LIF）的培养基中培养的ESC中β-连环蛋白出现波动，在这种培养基中关键多能性因子的蛋白质水平是异质性的。在2i+LIF培养基中，其有利于ESC在多能性的基础状态下增殖，许多多能性基因失去嵌合表达，我们发现存在不依赖Nanog的β-连环蛋白波动。总体而言，我们证明了Nanog和β-连环蛋白在重编程过程中建立原始多能性方面的协同作用以及它们在趋向分化的ESC中的相关异质性。
