miR-223 regulates endothelial to hematopoietic transition

摘要 自我更新的多能造血干细胞和祖细胞（HSPC）对于造血干细胞的基础和功能至关重要。 成人血液系统的终身维护。在胚胎发育过程中， 血管内皮细胞（EC）的一个亚群，称为生血内皮细胞（hemEC），获得造血 潜在的并产生HSPC，从背主动脉的腹侧壁出芽。不幸的是，监管机构 生血内皮细胞特化和HSPC从内皮形成的机制在很大程度上是不确定的。 最近，我们确定miR-223作为斑马鱼造血内皮细胞的新调节因子。斑马鱼和 小鼠miR-223突变胚胎的生血内皮细胞数量增加，导致成熟HSPC 从造血的开始到后期阶段的扩张。虽然我们的研究证实miR-223是一种新的 造血内皮细胞发育和HSPC生成的调节因子，特异性细胞事件 在这些过程中由miR-223调控的直接分子靶点仍然未知。转录组分析 来自斑马鱼和小鼠胚胎的野生型和miR-223突变体内皮细胞， 造血正在发生，揭示了miR-223靶基因富集了与蛋白质N- 糖基化有趣的是，已知miRNA在类似于EHT的过程中靶向糖基化酶， 如内皮细胞向间充质细胞转化和癌症转移。然而，是否miRNA依赖 糖基化调节延伸至EHT，HSPC诱导仍未研究。在这里，我们将测试 假设miR-223微调N-糖基化水平以控制内皮细胞到造血细胞命运 过渡

ABSTRACT Self-renewing, multipotent hematopoietic stem and progenitor cells (HSPCs) are essential for the foundation and lifetime maintenance of the adult blood system. Definitive HSPCs are born during embryonic development when a subset of vascular endothelial cells (ECs), called hemogenic endothelium (hemECs), acquire hematopoietic potential and give rise to HSPC that bud from the ventral wall of the dorsal aorta. Unfortunately, the regulators of hemogenic endothelial cell specification and HSPC formation from endothelium are largely undefined. Recently, we identified miR-223 as novel regulator of hemogenic endothelial cells in zebrafish. Zebrafish and mice miR-223 mutant embryos had an increased number hemogenic endothelial cells, resulting in mature HSPC expansion from the onset and into later stages of hematopoiesis. While our studies establish miR-223 as a novel regulatory factor of hemogenic endothelial cell development and HSPC generation, the specific cellular events and direct molecular targets regulated by miR-223 in these processes remain unknown. Transcriptome analysis of wild type and miR-223 mutant endothelial cells from zebrafish and mouse embryos, at stages when definitive hematopoiesis is occurring, revealed that miR-223 target-genes were enriched for genes relating to protein N- glycosylation. Interestingly, miRNAs are known to target glycosylation enzymes in processes analogous to EHT, such as endothelial-to-mesenchymal transition and cancer metastasis. However, whether miRNA-dependent glycosylation regulation extends to EHT and HSPC induction remains uninvestigated. Here, we will test the hypothesis that miR-223 fine tunes N-glycosylation levels to control endothelial to hematopoietic cell fate transition.