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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.

摘要自我更新、多潜能的造血干细胞和祖细胞(HSPC)对于终生维护成人血液系统。明确的HSPC在胚胎发育期间出生，当血管内皮细胞(ECs)的亚群，称为血源性内皮(HemECs)，可获得造血细胞从腹主动脉腹壁萌发的HSPC。不幸的是，监管机构血源性内皮细胞的特性和内皮细胞形成HSPC在很大程度上是不确定的。最近，我们发现miR-223是一种新的斑马鱼血源性内皮细胞调节因子。斑马鱼和小鼠miR-223突变胚胎的血源性内皮细胞数量增加，导致成熟的HSPC 从最初的造血期到后期的扩增。虽然我们的研究证明miR-223是一种新的血源性内皮细胞发育的调节因子和HSPC的产生、特异性细胞事件而miR-223在这些过程中调控的直接分子靶点仍不清楚。转录组分析斑马鱼和小鼠胚胎的野生型和miR-223突变内皮细胞造血发生，显示miR-223靶基因富含与N-蛋白相关的基因- 糖基化。有趣的是，已知miRNAs在类似于EHT的过程中针对糖基化酶，如内皮细胞向间充质细胞的转化和肿瘤转移。然而，是否依赖于miRNA 糖基化调节延伸到EHT，HSPC的诱导仍未被研究。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。