Regulation of Hemogenic Endothelial Cell Specification by microRna-223
Date of Award
Doctor of Philosophy (PhD)
Embryonic definitive hematopoiesis generates hematopoietic stem and progenitor cells (HSPCs) essential for the establishment and maintenance of the adult blood system. This process requires the specification of a subset of vascular endothelial cells to become blood-forming, or hemogenic, and the subsequent endothelial-to-hematopoietic transition (EHT) to generate HSPCs therefrom. The mechanisms that regulate these processes are under intensive investigation, as their recapitulation in vitro from human pluripotent stem cells has the potential to generate autologous HSPCs for clinical applications. In these studies, we identified microRNA-223 (miR-223) as a novel negative regulator of hemogenic endothelial cell (EC) specification and HSPC production. We found that miR-223 is enriched in hemogenic ECs and HSPCs in the mouse aorta-gonad-mesonephros region (AGM), and represses the generation of these cells during definitive hematopoiesis. Thus, loss of miR-223 leads to increased formation of hemogenic ECs and their generation of HSPCs, and this is associated with increased retinoic acid (RA) signaling in the AGM endothelium, which we previously found promotes hemogenic EC specification. Loss of miR-223 also promotes the generation of myeloid-biased hemogenic ECs and HSPCs, which results in an increased proportion of myeloid cells throughout embryonic development and postnatally into adulthood. We also found that chemical inhibition of N-glycome phenocopies miR-223-deficiency and miR-223 restrains hemogenic specification potentially by targeting N-glycogenes to regulate N-glycan biosynthesis. Collectively, our findings improve our understanding of hematopoiesis and may yield new targets for clinical therapy.
Wu, Yinyu, "Regulation of Hemogenic Endothelial Cell Specification by microRna-223" (2022). Yale Graduate School of Arts and Sciences Dissertations. 535.