Laboratory of Immunology, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, Republic of Korea.
Biochem Biophys Res Commun. 2012 Jul 13;423(4):750-6. doi: 10.1016/j.bbrc.2012.06.031. Epub 2012 Jun 15.
Bone morphogenetic proteins (BMPs) that belong to the transforming growth factor-β (TGF-β) superfamily cytokines, play crucial roles in hematopoiesis. However, roles of Smad6 in hematopoiesis remained unknown in contrast to the other inhibitory Smad (I-Smad), Smad7. Here we show that Smad6 inhibits erythropoiesis in human CD34(+) cord blood hematopoietic stem cells (HSCs). Smad6 was specifically expressed in CD34(+) cord blood HSCs, which was correlated with the expression of BMP2/4/6/7 and BMP type I receptor (BMPRI). BMP-specific receptor-regulated Smads (R-Smads), Smad1 and Smad5 in cooperation with Smad4 induced transcription of the Smad6 gene. Instead of affecting cell cycle, apoptosis, self-renewal, and stemness of CD34(+) cells, Smad6 knockdown enhanced, whereas Smad6 overexpression suppressed erythropoiesis in stem cell culture and colony formation assay. Consistently, Smad6 suppressed the expression of the genes essential for erythropoiesis, such as Kruppel-like factor 1 (erythroid) (KLF1/EKLF) and GATA binding protein 2 (GATA-2). Promoter analyses showed that Smad6 repressed Smad5/4-induced transcription of the Klf1 gene. Thus, our data suggest that Smad6 indirectly maintains stemness by preventing spontaneous erythropoiesis in HSCs.
骨形态发生蛋白（BMPs）属于转化生长因子-β（TGF-β）超家族细胞因子，在造血中发挥着关键作用。然而，与其他抑制性 Smad（I-Smad）Smad7 不同，Smad6 在造血中的作用尚不清楚。在这里，我们表明 Smad6 抑制了人 CD34+脐带血造血干细胞（HSCs）中的红细胞生成。Smad6 特异性表达于 CD34+脐带血 HSCs，与 BMP2/4/6/7 和 BMP 型 I 受体（BMPRI）的表达相关。BMP 特异性受体调节 Smads（R-Smads）Smad1 和 Smad5 与 Smad4 合作诱导 Smad6 基因的转录。Smad6 下调而非影响细胞周期、凋亡、自我更新和 CD34+细胞的干性，增强了干细胞培养和集落形成试验中的红细胞生成，而 Smad6 过表达则抑制了红细胞生成。一致地，Smad6 抑制了红细胞生成所必需的基因的表达，如 Kruppel 样因子 1（红细胞）（KLF1/EKLF）和 GATA 结合蛋白 2（GATA-2）。启动子分析表明，Smad6 抑制了 Smad5/4 诱导的 Klf1 基因转录。因此，我们的数据表明 Smad6 通过防止 HSCs 中自发的红细胞生成，间接地维持干细胞的干性。
