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
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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