RT Journal Article
SR Electronic
T1 The N-Glycome regulates the endothelial-to-hematopoietic transition
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 602912
DO 10.1101/602912
A1 Dionna M. Kasper
A1 Jared Hintzen
A1 Yinyu Wu
A1 Joey J. Ghersi
A1 Hanna K. Mandl
A1 Kevin E. Salinas
A1 William Armero
A1 Zhiheng He
A1 Ying Sheng
A1 Yixuan Xie
A1 Daniel W. Heindel
A1 Eon Joo Park
A1 William C. Sessa
A1 Lara K. Mahal
A1 Carlito Lebrilla
A1 Karen K. Hirschi
A1 Stefania Nicoli
YR 2020
UL http://biorxiv.org/content/early/2020/08/06/602912.abstract
AB Hematopoietic 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 Summary The N-glycan “sugar code” governs the hematopoietic fate of endothelial cells and regulates blood stem cell production in vivo.Competing Interest StatementThe authors have declared no competing interest.