Abstract
SummaryIt is now well-established that hematopoietic stem cells (HSCs) and progenitor cells originate from a specialized subset of endothelium, termed hemogenic endothelium (HE), via an endothelial-to-hematopoietic transition. However, the molecular mechanisms determining which endothelial progenitors possess this hemogenic potential are currently unknown. Here, we investigated the changes in hemogenic potential in endothelial progenitors at the early stages of embryonic development. Using an ETV2::GFP reporter mouse to isolate emerging endothelial progenitors, we observed a dramatic decrease in hemogenic potential between embryonic day (E)7.5 and E8.5. At the molecular level, Runx1 is expressed at much lower levels in E8.5 intra-embryonic progenitors, while Bmi1 expression is increased. Remarkably, the ectopic expression of Runx1 in these progenitors fully restores their hemogenic potential, as does the suppression of BMI1 function. Altogether, our data demonstrate that hemogenic competency in recently specified endothelial progenitors is restrained through the active silencing of Runx1 expression.
Highlights
Hematopoiesis emerges early in the vertebrate embryo and occurs in three major distinct waves (Costa et al, 2012)
To compare the hemogenic potential of E7.5 and E8.5 (EP) ETV2::GFP+ cell populations, E7.5 and E8.5 embryos were harvested and cells were sorted based on their FLK1+GFP+CD41À immuno-phenotype, followed by plating on OP9 stroma under conditions that support hemogenic endothelium (HE) growth and maturation (Figure 1B; Figure S1A)
A small fraction of CD41+ cells lost expression of both endothelial markers at the E8.5 stage. This revealed that the majority of CD41+ cells derived from E8.5 ETV2::GFP+FLK1+
Summary
Hematopoiesis emerges early in the vertebrate embryo and occurs in three major distinct waves (Costa et al, 2012). The two first waves take place in the extra-embryonic yolk sac (YS) between embryonic day (E)7.0 and E9.0 and give rise to primitive erythrocytes, macrophages, and megakaryocytes (Palis et al, 1999). The first site of intra-embryonic hematopoiesis is the. The AGM is the site where the first hematopoietic stem cells (HSCs) with long-term reconstituting and multi-lineage capacity emerge by E10.5 (Medvinsky et al, 1993; Mu€ller et al, 1994). Functional HSCs are detected a day later in the fetal liver (FL), placenta, and YS (Gekas et al, 2005; Medvinsky and Dzierzak, 1996)
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