Rao Jyoti, Pfeiffer Martin J, Frank Stefan, Adachi Kenjiro, Piccini Ilaria, Quaranta Roberto, Araúzo-Bravo Marcos, Schwarz Juliane, Schade Dennis, Leidel Sebastian, Schöler Hans R, Seebohm Guiscard, Greber Boris
Human Stem Cell Pluripotency Laboratory, Max Planck Institute for Molecular Biomedicine, 48149 Münster, Germany; Chemical Genomics Centre of the Max Planck Society, 44227 Dortmund, Germany.
Department of Cell and Developmental Biology, Max Planck Institute for Molecular Biomedicine, 48149 Münster, Germany.
Cell Stem Cell. 2016 Mar 3;18(3):341-53. doi: 10.1016/j.stem.2015.11.019. Epub 2015 Dec 31.
Cardiac induction requires stepwise integration of BMP and WNT pathway activity. Human embryonic stem cells (hESCs) are developmentally and clinically relevant for studying the poorly understood molecular mechanisms downstream of these cascades. We show that BMP and WNT signaling drive cardiac specification by removing sequential roadblocks that otherwise redirect hESC differentiation toward competing fates, rather than activating a cardiac program per se. First, BMP and WNT signals pattern mesendoderm through cooperative repression of SOX2, a potent mesoderm antagonist. BMP signaling promotes miRNA-877 maturation to induce SOX2 mRNA degradation, while WNT-driven EOMES induction transcriptionally represses SOX2. Following mesoderm formation, cardiac differentiation requires inhibition of WNT activity. We found that WNT inhibition serves to restrict expression of anti-cardiac regulators MSX1 and CDX2/1. Conversely, their simultaneous disruption partially abrogates the requirement for WNT inactivation. These results suggest that human cardiac induction depends on multi-stage repression of alternate lineages, with implications for deriving expandable cardiac stem cells.
心脏诱导需要BMP和WNT信号通路活性的逐步整合。人类胚胎干细胞（hESCs）在发育和临床上对于研究这些级联反应下游了解甚少的分子机制具有重要意义。我们发现，BMP和WNT信号通过消除一系列阻碍因素来驱动心脏特化，这些阻碍因素否则会使hESC分化转向竞争命运，而不是直接激活心脏程序本身。首先，BMP和WNT信号通过协同抑制SOX2（一种有效的中胚层拮抗剂）来调控中胚层的形成。BMP信号促进miRNA - 877成熟以诱导SOX2 mRNA降解，而WNT驱动的EOMES诱导则通过转录抑制SOX2。中胚层形成后，心脏分化需要抑制WNT活性。我们发现，抑制WNT可限制抗心脏调节因子MSX1和CDX2/1的表达。相反，同时破坏它们可部分消除对WNT失活的需求。这些结果表明，人类心脏诱导依赖于对替代谱系的多阶段抑制，这对于获得可扩增的心脏干细胞具有重要意义。
