miR-223 regulates endothelial to hematopoietic transition

miR-223 调节内皮细胞向造血细胞的转变

• 批准号: 10763971
• 负责人: Karen Kemper Hirschi
• 金额: $ 8.85万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-15 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10763971
• 关键词: Adult; Affect; Aorta; Biological Assay; Biological Process; Blood; Cell physiology; Cells; Development; Dorsal; Embryo; Embryonic Development; Endothelial Cells; Endothelium; Enzymes; Event; Exhibits; Foundations; Gene Expression Profile; Gene Silencing; Generations; Genes; Genetic; Glycols; Glycoproteins; Hematopoiesis; Hematopoietic; Hematopoietic Stem Cell Specification; Hematopoietic stem cells; Impairment; In Vitro; Life; Maintenance; Mammals; Mesenchymal; Messenger RNA; MicroRNAs; Modification; Molecular; Molecular Target; Mus; Neoplasm Metastasis; Optics; Pathway interactions; Pattern; Phenocopy; Phenotype; Polysaccharides; Post-Translational Protein Processing; Process; Production; Proliferating; Protein Glycosylation; Proteins; Proteomics; Regulation; Role; Specific qualifier value; Stem Cell Development; System; Testing; Therapeutic; Universities; Uterus; Vascular Endothelial Cell; Visualization; Zebrafish; cell type; glycosylation; hematopoietic transplantation; hemogenic endothelium; large scale production; link protein; molecular phenotype; mouse genetics; mutant; neoplastic cell; novel; pharmacologic; postnatal; posttranscriptional; prevent; regenerative therapy; self-renewal; success; transcriptome

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.

抽象的 自我更新、多能造血干细胞和祖细胞 (HSPC) 对于基础和发育至关重要 成人血液系统的终生维护。决定性 HSPC 在胚胎发育过程中诞生，当 血管内皮细胞 (EC) 的子集，称为造血内皮 (hemEC)，获得造血功能 潜力并产生从背主动脉腹壁出芽的 HSPC。不幸的是，监管者 造血内皮细胞规格和内皮细胞 HSPC 形成的机制在很大程度上尚不清楚。 最近，我们发现 miR-223 是斑马鱼造血内皮细胞的新型调节因子。斑马鱼和 miR-223突变小鼠胚胎的造血内皮细胞数量增加，从而产生成熟的HSPC 从造血的开始到后期的扩张。虽然我们的研究表明 miR-223 是一种新型 造血内皮细胞发育和HSPC生成的调节因子，特定的细胞事件 在这些过程中 miR-223 调节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 突变内皮细胞，在确定的阶段 造血作用正在发生，揭示 miR-223 靶基因富含与蛋白质 N-相关的基因 糖基化。有趣的是，已知 miRNA 可以在类似于 EHT 的过程中靶向糖基化酶， 例如内皮间质转化和癌症转移。然而，是否依赖 miRNA 糖基化调节延伸至 EHT 和 HSPC 诱导仍未得到研究。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的命运 过渡。