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

Kasper, DM Hintzen, J, Wu Y, Ghersi, JJ, Mandl HK, Salinas, KE, Armero, W, He Z, Sheng, Y, Xie, Y, Heindel DW, Park EJ, Sessa, WC, Mahal LK, Lebrilla, C, Hirschi, Nicoli, S. Science . 2020 Dec 4;370(6521):1186-1191. PMID: 33273096

Definitive hematopoietic stem and progenitor cells (HSPCs) arise from the transdifferentiation of hemogenic endothelial cells (hemECs). The mechanisms of this endothelial-to-hematopoietic transition (EHT) are poorly understood. We show that microRNA-223 (miR-223)-mediated regulation of N-glycan biosynthesis in endothelial cells (ECs) regulates EHT. miR-223 is enriched in hemECs and in oligopotent nascent HSPCs. miR-223 restricts the EHT of lymphoid-myeloid lineages by suppressing the mannosyltransferase <em>alg2</em> and sialyltransferase <em>st3gal2</em>, two enzymes involved in protein N-glycosylation. ECs that lack miR-223 showed a decrease of high mannose versus sialylated sugars on N-glycoproteins such as the metalloprotease Adam10. EC-specific expression of an N-glycan Adam10 mutant or of the N-glycoenzymes phenocopied miR-223 mutant defects. Thus, the N-glycome is an intrinsic regulator of EHT, serving as a key determinant of the hematopoietic fate.

This project was partially funded by Yale University School of Medicine YCCEH Pilot and Feasability NIDDK U54 Funding.

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Last updated: 04-06-2021