The N-Glycome regulates the endothelial-to-hematopoietic transition
Glycosylation
beta-Galactoside alpha-2,3-Sialyltransferase
3-Sialyltransferase
General Science & Technology
Genetically Modified
Regenerative Medicine
Mannosyltransferases
Animals, Genetically Modified
Medicinal and Biomolecular Chemistry
ADAM10 Protein
beta-Galactoside alpha-2
Genes, Reporter
Polysaccharides
Genetics
2.1 Biological and endogenous factors
Animals
Cell Lineage
Aetiology
Reporter
Glycomics
Zebrafish
Glycoproteins
Endothelial Cells
Hematology
Biological Sciences
Stem Cell Research
Hematopoietic Stem Cells
Sialyltransferases
3. Good health
MicroRNAs
Genes
Chemical Sciences
Cell Transdifferentiation
Stem Cell Research - Nonembryonic - Non-Human
DOI:
10.1101/602912
Publication Date:
2019-04-10T00:06:40Z
AUTHORS (17)
ABSTRACT
AbstractHematopoietic stem and progenitor cells (HSPCs) that establish and maintain the blood system in adult vertebrates arise from the transdifferentiation of hemogenic endothelial cells (hemECs) during embryogenesis. This endothelial-to-hematopoietic transition (EHT) is tightly regulated, but the mechanisms are poorly understood. Here, we show that microRNA (miR)-223-mediated regulation of N-glycan biosynthesis in endothelial cells (ECs) regulates EHT. Single cell RNA-sequencing revealed that miR-223 is enriched in hemECs and in oligopotent nascent HSPCs. miR-223 restricts the EHT of lymphoid/myeloid lineages by suppressing the expression of mannosyltransferase alg2 and sialyltransferase st3gal2, two enzymes involved in N-linked protein glycosylation. High-throughput glycomics of ECs lacking miR-223 showed a decrease of high mannose versus sialylated complex/hybrid sugars on N-glycoproteins involved in EHT such as the metalloprotease Adam10. Endothelial-specific expression of an N-glycan Adam10 mutant or of the N-glycoenzymes phenocopied the aberrant HSPC production of miR-223 mutants. Thus, the N-glycome plays a previously unappreciated role as an intrinsic regulator of EHT, with specific mannose and sialic acid modifications serving as key endothelial determinants of their hematopoietic fate.One Sentence SummaryThe N-glycan “sugar code” governs the hematopoietic fate of endothelial cells and regulates blood stem cell production in vivo.
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CITATIONS (1)
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