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：
10348182
负责人：
Karen Kemper Hirschi
金额：
$ 69.23万
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 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10348182
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 cells Impairment In Vitro Life Maintenance Mammals Mesenchymal Messenger RNA MicroRNAs Modification Molecular Molecular Target Mus Neoplasm Metastasis Optics Pathway interactions Pattern Pharmacology Phenocopy Phenotype Polysaccharides Post-Translational Protein Processing Process Production Protein Glycosylation Proteins Proteomics Regulation Role Stem Cell Development System Testing Therapeutic Universities Uterus Vascular Endothelial Cell Visualization Zebrafish cell type glycosylation hematopoietic transplantation hemogenic endothelium link protein molecular phenotype mouse genetics mutant neoplastic cell novel postnatal 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，多能造血茎和祖细胞（HSPC）对于基础和成人血液系统的终生维护。确定的HSPC是在胚胎开发期间出生的血管内皮细胞（EC）的子集，称为血液内皮（Hemecs），获得造血潜在的并引起从背主动脉的腹壁芽的HSPC。不幸的是，监管机构内皮的血液内皮细胞规范和HSPC形成的大部分是不确定的。最近，我们将miR-223确定为斑马鱼中血质内皮细胞的新型调节剂。斑马鱼和小鼠miR-223突变体胚胎的血肿内皮细胞数量增加，导致成熟的HSPC 从发作到造血的后期膨胀。而我们的研究将miR-223建立为新颖血质内皮细胞发育和HSPC产生（特定细胞事件）的调节因子在这些过程中由miR-223调节的直接分子靶标仍然未知。转录组分析从斑马鱼和小鼠胚胎的野生型和miR-223突变体内皮细胞造血发生了，发现miR-223靶基因富含与蛋白N-有关的基因糖基化。有趣的是，已知miRNA靶向类似于EHT的过程中的糖基化酶例如内皮到间质转变和癌症转移。但是，是否取决于miRNA 糖基化调节延伸至EHT，HSPC诱导仍未进行研究。在这里，我们将测试 miR-223微调N-糖基化水平以控制造血细胞命运的假设过渡。