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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK118728-01A1
Application #
9882072
Study Section
Molecular and Cellular Hematology Study Section (MCH)
Program Officer
Bishop, Terry Rogers
Project Start
2020-04-15
Project End
2024-01-31
Budget Start
2020-04-15
Budget End
2021-01-31
Support Year
1
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520