Lillehei Heart Institute, Department of Medicine, University of Minnesota, Minneapolis, MN, USA.
Exp Hematol. 2012 Oct;40(10):837-46. doi: 10.1016/j.exphem.2012.06.007. Epub 2012 Jun 19.
Increasing evidence points to endoglin (Eng), an accessory receptor for the transforming growth factor-β superfamily commonly associated with the endothelial lineage, as an important regulator of the hematopoietic lineage. We have shown that lack of Eng results in reduced numbers of primitive erythroid colonies as well as downregulation of key hematopoietic genes. To determine the effect of Eng overexpression in hematopoietic development, we generated a doxycycline-inducible embryonic stem cell line. Our results demonstrate that induction of Eng during embryoid body differentiation leads to a significant increase in the frequency of hematopoietic progenitors, in particular, the erythroid lineage, which correlated with upregulation of Scl, Gata1, Runx1, and embryonic globin. Interestingly, activation of the hematopoietic program happened at the expense of endothelial and cardiac cells, as differentiation into these mesoderm lineages was compromised. Eng-induced enhanced erythroid activity was accompanied by high levels of Smad1 phosphorylation. This effect was attenuated by addition of a bone morphogenetic protein (BMP) signaling inhibitor to these cultures. Among the BMPs, BMP4 is well known for its role in hematopoietic specification from mesoderm by promoting expression of several hematopoietic genes, including Scl. Because Scl is considered the master regulator of the hematopoietic program, we investigated whether Scl would be capable of rescuing the defective hematopoietic phenotype observed in Eng(-/-) embryonic stem cells. Scl expression in Eng-deficient embryonic stem cells resulted in increased erythroid colony-forming activity and upregulation of Gata1 and Gata2, positioning Eng upstream of Scl. Taken together, these findings support the premise that Eng modulates the hematopoietic transcriptional network, most likely through regulation of BMP4 signaling.
越来越多的证据表明，内皮糖蛋白（Eng）是转化生长因子-β超家族的辅助受体，通常与内皮谱系相关，是造血谱系的重要调节因子。我们已经表明，缺乏 Eng 会导致原始红细胞集落数量减少，以及关键造血基因的下调。为了确定 Eng 过表达对造血发育的影响，我们生成了一种强力霉素诱导的胚胎干细胞系。我们的结果表明，在胚状体分化过程中诱导 Eng 的表达会导致造血祖细胞的频率显著增加，特别是红系，这与 Scl、Gata1、Runx1 和胚胎球蛋白的上调相关。有趣的是，造血程序的激活是以牺牲内皮细胞和心肌细胞为代价的，因为这些中胚层谱系的分化受到了损害。Eng 诱导的增强的红细胞活性伴随着高水平的 Smad1 磷酸化。向这些培养物中添加骨形态发生蛋白（BMP）信号抑制剂可减弱这种效应。在 BMPs 中，BMP4 因其通过促进包括 Scl 在内的几种造血基因的表达，在从中胚层造血特化中的作用而闻名。由于 Scl 被认为是造血程序的主调控因子，我们研究了 Scl 是否能够挽救 Eng(-/-)胚胎干细胞中观察到的造血缺陷表型。Scl 在 Eng 缺陷型胚胎干细胞中的表达导致红细胞集落形成活性增加和 Gata1 和 Gata2 的上调，使 Eng 位于 Scl 的上游。总之，这些发现支持了这样一个前提，即 Eng 调节造血转录网络，很可能是通过调节 BMP4 信号。
