Augustin Iris, Dewi Dyah L, Hundshammer Jennifer, Erdmann Gerrit, Kerr Grainne, Boutros Michael
German Cancer Research Center (DKFZ), Division of Signaling and Functional Genomics, and Department of Cell and Molecular Biology, Medical Faculty Mannheim, Heidelberg University, Heidelberg 69120, Germany.
NMI TT Naturwissenschaftliches und Medizinisches Institut Technologie Transfer GmbH Pharmaservices, Berlin 13353, Germany.
Sci Signal. 2017 Jan 10;10(461):eaah6829. doi: 10.1126/scisignal.aah6829.
Wnt signaling plays an important role in the self-renewal and differentiation of stem cells. The secretion of Wnt ligands requires Evi (also known as Wls). Genetically ablating Evi provides an experimental approach to studying the consequence of depleting all redundant Wnt proteins, and overexpressing Evi enables a nonspecific means of increasing Wnt signaling. We generated Evi-deficient and Evi-overexpressing mouse embryonic stem cells (ESCs) to analyze the role of autocrine Wnt production in self-renewal and differentiation. Self-renewal was reduced in Evi-deficient ESCs and increased in Evi-overexpressing ESCs in the absence of leukemia inhibitory factor, which supports the self-renewal of ESCs. The differentiation of ESCs into cardiomyocytes was enhanced when Evi was overexpressed and teratoma formation and growth of Evi-deficient ESCs in vivo were impaired, indicating that autocrine Wnt ligands were necessary for ESC differentiation and survival. ESCs lacking autocrine Wnt signaling had mitotic defects and showed genomic instability. Together, our study demonstrates that autocrine Wnt secretion is important for the survival, chromosomal stability, differentiation, and tumorigenic potential of ESCs.
Wnt信号通路在干细胞的自我更新和分化中起着重要作用。Wnt配体的分泌需要Evi（也称为Wls）。通过基因敲除Evi提供了一种研究耗尽所有冗余Wnt蛋白后果的实验方法，而过表达Evi则是增加Wnt信号的一种非特异性手段。我们构建了Evi缺陷型和Evi过表达型小鼠胚胎干细胞（ESC），以分析自分泌Wnt产生在自我更新和分化中的作用。在缺乏支持ESC自我更新的白血病抑制因子的情况下，Evi缺陷型ESC的自我更新能力降低，而Evi过表达型ESC的自我更新能力增强。当Evi过表达时，ESC向心肌细胞的分化增强，并且Evi缺陷型ESC在体内的畸胎瘤形成和生长受到损害，这表明自分泌Wnt配体对于ESC的分化和存活是必需的。缺乏自分泌Wnt信号的ESC存在有丝分裂缺陷并表现出基因组不稳定。总之，我们的研究表明自分泌Wnt分泌对于ESC的存活、染色体稳定性、分化和致瘤潜力很重要。
