Research Article

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

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Science  04 Dec 2020:
Vol. 370, Issue 6521, pp. 1186-1191
DOI: 10.1126/science.aaz2121

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Sugar code regulates blood stem cells

During embryonic development, blood stem cells are derived from vascular endothelial cells that line the walls of developing arteries. The transition from endothelial cells to blood stem cells is highly regulated and restricted to a small portion of endothelial cells during a brief period of time. The mechanisms regulating this transition are also poorly understood. Kasper et al. found that microRNA-223 intrinsically restrains the vascular hematopoietic transition by regulating N-glycan biosynthesis to restrict hematopoietic stem and progenitor cell production and differentiation. Genetics or chemicals could be used to alter the sugar code and change the efficiency of blood production in embryos. Thus, genetically or pharmacologically altering N-glycan biosynthesis in endothelial cells could improve the efficiency of the production of blood stem cells, which could then be used to treat blood diseases such as leukemia.

Science, this issue p. 1186


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.

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