miR-223 regulates endothelial to hematopoietic transition

miR-223 调节内皮细胞向造血细胞的转变

基本信息

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
项目类别：
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

项目摘要

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。决定性的 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明确。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。