1] Urologische Klinik und Zentrale Klinische Forschung, Klinikum der Universität Freiburg, Breisacher Strasse 66, 79106 Freiburg, Germany [2].
Urologische Klinik und Zentrale Klinische Forschung, Klinikum der Universität Freiburg, Breisacher Strasse 66, 79106 Freiburg, Germany.
Nat Commun. 2014;5:3174. doi: 10.1038/ncomms4174.
Propagation and differentiation of stem cell populations are tightly regulated to provide sufficient cell numbers for tissue formation while maintaining the stem cell pool. Embryonic parts of the mammalian placenta are generated from differentiating trophoblast stem cells (TSCs) invading the maternal decidua. Here we demonstrate that lysine-specific demethylase 1 (Lsd1) regulates differentiation onset of TSCs. Deletion of Lsd1 in mice results in the reduction of TSC number, diminished formation of trophectoderm tissues and early embryonic lethality. Lsd1-deficient TSCs display features of differentiation initiation, including alterations of cell morphology, and increased migration and invasion. We show that increased TSC motility is mediated by the premature expression of the transcription factor Ovol2 that is directly repressed by Lsd1 in undifferentiated cells. In summary, our data demonstrate that the epigenetic modifier Lsd1 functions as a gatekeeper for the differentiation onset of TSCs, whereby differentiation-associated cell migration is controlled by the transcription factor Ovol2.
干细胞群体的增殖和分化受到严格调控，以提供足够的细胞数量用于组织形成，同时保持干细胞池。哺乳动物胎盘的胚胎部分是由分化的滋养层干细胞（TSC）侵入母体蜕膜而产生的。在这里，我们证明赖氨酸特异性去甲基化酶 1（Lsd1）调节 TSC 的分化起始。在小鼠中删除 Lsd1 会导致 TSC 数量减少、滋养外胚层组织形成减少和早期胚胎致死。Lsd1 缺陷型 TSC 表现出分化起始的特征，包括细胞形态的改变，以及迁移和侵袭能力的增加。我们表明，TSC 运动性的增加是由转录因子 Ovol2 的过早表达介导的，Ovol2 在未分化细胞中被 Lsd1 直接抑制。总之，我们的数据表明，表观遗传修饰剂 Lsd1 作为 TSC 分化起始的守门员，通过转录因子 Ovol2 控制分化相关的细胞迁移。
