Embryonic stromal clones reveal developmental regulators of definitive hematopoietic stem cells
Embryonic stromal clones reveal developmental regulators of definitive hematopoietic stem cells
复制标题
DOI：
10.1073/pnas.0706923105
复制
发表时间：
2007-12-26
影响因子：
11.1
通讯作者：
Dzierzak, Elaine
中科院分区：
文献类型：
--
作者：
Durand, Charles;Robin, Catherine;Dzierzak, Elaine
造血干细胞（HSC）的自我更新和分化是通过与周围微环境的细胞和分子相互作用来调节的。在个体发育过程中，AGM区域自主产生第一个HSC，并作为第一个支持HSC的微环境。由于AGM微环境的分子身份尚不清楚，我们检查了两个密切相关的AGM基质克隆，它们差异性地支持HSC。表达分析鉴定了三种推定的HSC调节因子，β-NGF（神经营养因子）、MIP-1 γ（C-C趋化因子家族成员）和Bmp 4（TGF-β家族成员）。我们在这里表明，这三个因素，当添加到AGM外植体培养，增强AGM HSC的体内再生能力。Bmp 4对AGM HSC的作用被进一步研究，因为该因子在小鼠胚胎中的中胚层和原始红细胞生成阶段起作用。在这篇报道中，我们显示富集Ell AGM HSC表达Bmp受体，且其活性可被一种Bmp拮抗剂gremlin抑制。此外，我们的研究结果揭示了Bmp 4表达的焦点在间充质的基础HSC含有主动脉簇在E11。我们认为Bmp 4在HSC的调节中起着相对较晚的作用，因为它们出现在妊娠中期AGM。
Hematopoietic stem cell (HSC) self-renewal and differentiation is regulated by cellular and molecular interactions with the surrounding microenvironment. During ontogeny, the aorta-gonad-mesonephros (AGM) region autonomously generates the first HSCs and serves as the first HSC-supportive microenvironment. Because the molecular identity of the AGM microenvironment is as yet unclear, we examined two closely related AGM stromal clones that differentially support HSCs. Expression analyses identified three putative HSC regulatory factors, beta-NGF (a neurotrophic factor), MIP-1 gamma (a C-C chemokine family member) and Bmp4 (a TGF-beta family member). We show here that these three factors, when added to AGM explant cultures, enhance the in vivo repopulating ability of AGM HSCs. The effects of Bmp4 on AGM HSCs were further studied because this factor acts at the mesodermal and primitive erythropoietic stages in the mouse embryo. in this report, we show that enriched Ell AGM HSCs express Bmp receptors and can be inhibited in their activity by gremlin, a Bmp antagonist. Moreover, our results reveal a focal point of Bmp4 expression in the mesenchyme underlying HSC containing aortic clusters at Ell. We suggest that Bmp4 plays a relatively late role in the regulation of HSCs as they emerge in the midgestation AGM.