Abstract
SummaryHematopoietic stem cells (HSCs) first emerge in the embryonic aorta-gonad-mesonephros (AGM) region. Studies of model organisms defined intersecting signaling pathways that converge to promote HSC emergence predominantly in the ventral domain of the dorsal aorta. Much less is known about mechanisms driving HSC development in humans. Here, to identify secreted signals underlying human HSC development, we combined spatial transcriptomics analysis of dorsoventral polarized signaling in the aorta with gene expression profiling of sorted cell populations and single cells. Our analysis revealed a subset of aortic endothelial cells with a downregulated arterial signature and a predicted lineage relationship with the emerging HSC/progenitor population. Analysis of the ventrally polarized molecular landscape identified endothelin 1 as an important secreted regulator of human HSC development. The obtained gene expression datasets will inform future studies on mechanisms of HSC development in vivo and on generation of clinically relevant HSCs in vitro.
Highlights
The first definitive hematopoietic stem cells (HSCs) that give rise to the adult hematopoietic system in mouse and human emerge in the embryonic aorta-gonad-mesonephros (AGM) region (Medvinsky and Dzierzak, 1996; Ivanovs et al, 2011; de Bruijn et al, 2000)
Using laser capture microdissection coupled with RNA sequencing (LCM-seq), we investigated dorsal-ventral (D-V) molecular differences across the dorsal aorta (Ao) with a focus on cell layers close to intra-aortic hematopoietic cell clusters (IAHCs) formation
Transverse cryosections of CS16–CS17 embryos were taken between the liver caudal border and the midgut loop (Figures 1A and S1A), where IAHCs/Hematopoietic stem cells (HSCs) predominantly emerge (Tavian et al, 1996; Tavian et al, 1999; Easterbrook et al, 2019)
Summary
The first definitive hematopoietic stem cells (HSCs) that give rise to the adult hematopoietic system in mouse and human emerge in the embryonic aorta-gonad-mesonephros (AGM) region (Medvinsky and Dzierzak, 1996; Ivanovs et al, 2011; de Bruijn et al, 2000). IAHCs/HSCs are formed through transition of the aortic endothelium toward the hematopoietic fate in a process termed endothelial-to-hematopoietic transition (EHT) (Jaffredo et al, 1998; Zovein et al, 2008; Medvinsky et al, 2011; Batsivari et al, 2017; Chen et al, 2009; Taoudi et al, 2008; Kissa and Herbomel, 2010; Bertrand et al, 2010). Definitive HSCs emerge between Carnegie stage 14 (CS14) and CS17 (postovulatory days 32–41) (Ivanovs et al, 2011), which overlaps with the time of appearance of IAHCs (Tavian et al, 1996, 1999). Recent single-cell transcriptomics analysis at earlier CS12–CS14 (postovulatory days 27–32) indicated a lineage relationship between human endothelium and hematopoietic stem and progenitor cells (HSPCs) (Zeng et al, 2019)
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