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 alg2 and sialyltransferase st3gal2, 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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