Abstract
SummaryHematopoietic stem cells (HSCs) emerge during development from the vascular wall of the main embryonic arteries. The onset of circulation triggers several processes that provide critical external factors for HSC generation. Nevertheless, it is not fully understood how and when the onset of circulation affects HSC emergence. Here we show that in Ncx1−/− mouse embryos devoid of circulation the HSC lineage develops until the phenotypic pro-HSC stage. However, these cells reside in an abnormal microenvironment, fail to activate the hematopoietic program downstream of Runx1, and are functionally impaired. Single-cell transcriptomics shows that during the endothelial-to-hematopoietic transition, Ncx1−/− cells fail to undergo a glycolysis to oxidative phosphorylation metabolic switch present in wild-type cells. Interestingly, experimental activation of glycolysis results in decreased intraembryonic hematopoiesis. Our results suggest that the onset of circulation triggers metabolic changes that allow HSC generation to proceed.
Highlights
Hematopoietic stem cells (HSCs) have the capacity to maintain all blood cell lineages during adult life
This places the specification of the HSC lineage around E9.5 (Rybtsov et al, 2014; Swiers et al, 2013), a time point that coincides with major changes in the developing mouse embryo, including the establishment of unidirectional blood flow (McGrath et al, 2003)
Through in vivo and ex vivo perturbation of glycolysis, we demonstrated that this metabolic switch is required for normal differentiation of intraembryonic hematopoietic progenitors
Summary
Hematopoietic stem cells (HSCs) have the capacity to maintain all blood cell lineages during adult life. The HSC lineage diverges from the HE with the emergence of pro-HSC at E9.5, which develop via pre-HSC type I and II into fully functional definitive HSCs at E11.5 (Rybtsov et al, 2014; Rybtsov et al, 2011; Taoudi et al, 2008). This places the specification of the HSC lineage around E9.5 (Rybtsov et al, 2014; Swiers et al, 2013), a time point that coincides with major changes in the developing mouse embryo, including the establishment of unidirectional blood flow (McGrath et al, 2003). The onset of circulation is an important extrinsic regulator of blood cell generation in vitro and in vivo (Adamo et al, 2009; Lundin et al, 2020; North et al, 2009)
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