1005 – REGULATION OF HEMATOPOIETIC STEM CELL BIRTH IN THE EMBRYONIC AORTA

Abstract

In vertebrates, hematopoietic stem cell (HSC) emergence mainly occurs in the dorsal aorta of the embryo. HSCs arise from hemogenic endothelial (HE) cells via an endothelial-to-hematopoietic transition (EHT) and the formation of intra-aortic hematopoietic clusters (IAHCs). The molecular events controlling endothelial specification, EHT and IAHC formation, as it occurs <i>in vivo</i> inside the aorta, are very complex and still poorly understood. The defined location of IAHCs/HSCs within the aortic niche regulates their fate, behaviour, and molecular identity via a complex extrinsic regulation. We made use of genome-wide RNA sequencing and tomography sequencing to explore the molecular characteristics and key components of IAHCs and precursors and the complexity of the aortic microenvironment landscape. Through interspecies comparative RNA sequencing analyses of zebrafish, chicken, mouse, and human embryos, we identified novel conserved processes that control HSC generation and mapped interactions between the niche and IAHCs. Among the various factors interacting to spatiotemporally regulate HSC generation <i>in vivo,</i> we functionally identified the niche-secreted ligand ADM and its IAHCs expressed receptor RAMP2, as well as SVEP1. Next to cell-extrinsic regulators, we also recently highlighted the important role of so far unexplored cytoskeletal rearrangements and microtubule dynamics regulation during EHT, HSC precursor maturation and self-renewal. Understanding the different cellular and molecular aspects that regulate HSC birth <i>in vivo</i> will pave the way for improved HSC production <i>in vitro</i> and clinical cell therapy.