The N-Glycome regulates the endothelial-to-hematopoietic transition

• DOI: 10.1101/602912
• Publication Date: 2019-04-10T00:06:40Z
• Authors: Dionna M. Kasper; Jared Hintzen; Yinyu Wu; Joey J. Ghersi; Hanna K. Mandl; Kevin E. Salinas; William Armero; Zhiheng He; Ying Sheng; Yixuan Xie; Daniel W. Heindel; Eon Joo Park; William C. Sessa; Lara K. Mahal; Carlito Lebrilla; Karen K. Hirschi; Stefania Nicoli
• Keywords: Glycome; Glycomics; Hematopoietic stem cell

Abstract Hematopoietic stem and progenitor cells (HSPCs) that establish maintain the blood system in adult vertebrates arise from transdifferentiation of hemogenic endothelial (hemECs) during embryogenesis. This endothelial-to-hematopoietic transition (EHT) is tightly regulated, but mechanisms are poorly understood. Here, we show microRNA (miR)-223-mediated regulation N-glycan biosynthesis (ECs) regulates EHT. Single cell RNA-sequencing revealed miR-223 enriched hemECs oligopotent nascent HSPCs. restricts EHT lymphoid/myeloid lineages by suppressing expression mannosyltransferase alg2 sialyltransferase st3gal2 , two enzymes involved N-linked protein glycosylation. High-throughput glycomics ECs lacking showed a decrease high mannose versus sialylated complex/hybrid sugars on N-glycoproteins such as metalloprotease Adam10. Endothelial-specific an Adam10 mutant or N-glycoenzymes phenocopied aberrant HSPC production mutants. Thus, N-glycome plays previously unappreciated role intrinsic regulator EHT, with specific sialic acid modifications serving key determinants their hematopoietic fate. One Sentence Summary The “sugar code” governs fate vivo.