MEKK3 signaling in hemogenic endothelium

项目摘要 胚胎定形造血是由内皮-造血转变启动的 (EHT)其中内皮细胞改变命运成为造血祖细胞和干细胞， 细胞在哺乳动物中，EHT有两个主要部位，卵黄囊脉管系统和 胚胎的主要动脉（背主动脉、卵黄动脉、脐动脉）。虽然这一过程 EHT是高度保守的，是所有脊椎动物造血所必需的， 控制血管内皮细胞向生血内皮细胞转化的信号 细胞知之甚少。最近的研究表明血流动力学剪切力 和炎症细胞因子在促进EHT，但如何这些不同的信号刺激 生血内皮的形成仍然未知。我们先前已经 证明MEKK 3 MAPK通路介导内皮细胞对 炎症细胞因子和血流动力学剪切力，在很大程度上是通过增加 KLF 2和KLF 4转录因子的表达。我们的初步研究 证明MEKK 3或KLF 2 + KLF 4的内皮损失导致致死性胎儿贫血 卵黄囊和胚胎EHT均失败。这项提案将考验 假设MEKK 3-KLF 2/4信号通过以下途径整合了内皮细胞刺激： 细胞因子和流体力触发EHT和确定的造血作用的开始。 这些研究有望对启动EHT的信号产生新的见解， 这些发现可用于产生新的造血干细胞和祖细胞， 治疗的目的。

Project Summary Embryonic definitive hematopoiesis is initiated by endothelial-hematopoietic transition (EHT) in which endothelial cells alter fate to become hematopoietic progenitors and stem cells. In mammals there are two major sites of EHT, the yolk sac vasculature and the major arteries of the embryo (dorsal aorta, vitelline, umbilical). Although the process of EHT is highly conserved and required for definitive hematopoiesis in all vertebrates, the signals that control the conversion of vascular endothelial cells to hemogenic endothelial cells are poorly understood. Recent studies have implicated hemodynamic shear forces and inflammatory cytokines in promoting EHT, but how these diverse signals stimulate the formation of hemogenic endothelium remains unknown. We have previously demonstrated that the MEKK3 MAPK pathway mediates endothelial cell responses to both inflammatory cytokines and hemodynamic shear forces, in large part by increasing expression of the KLF2 and KLF4 transcription factors. Our preliminary studies demonstrate that endothelial loss of MEKK3 or KLF2+KLF4 results in lethal fetal anemia and failure of EHT in both the yolk sac and embryo. This proposal will test the hypothesis that MEKK3-KLF2/4 signaling integrates endothelial cell stimulation by cytokines and fluid forces to trigger EHT and the onset of definitive hematopoiesis. These studies are expected to yield new insight into the signals that initiate EHT, findings that may be used to generate new hematopoietic stem and progenitor cells for therapeutic purposes later in life.