Self-renewing, multipotent hematopoietic stem and progenitor cells (HSPCs) are essential for the foundation and lifetime maintenance of the adult blood system. 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. miR-223 mutant zebrafish embryos had an increased number hemogenic endothelial cells, resulting in mature HSPC expansion from the onset and into later stages of hematopoiesis. We also found that miR-223 deficiency in mouse embryos lead to increased hemogenic endothelial cell formation. 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. Ultimately, we will combine mouse genetics with the optical clarity and high accessibility of the zebrafish model to discover novel mechanisms of hemogenic endothelial cell specification and HSPC formation. Discovery of new molecular pathways is imperative to overcoming current obstacles to mass-production of HSPCs from human endothelial cells for blood regenerative therapies
Self-renewing, multipotent hematopoietic stem and progenitor cells (HSPCs) are essential for the foundation and lifetime maintenance of the adult blood system. Here we will place miR-223 as a novel regulator of HSPC formation from endothelium.
