A critical role for endoglin in the emergence of blood during embryonic development

Abstract

Much remains unknown about the signals that induce early mesoderm to initiate hematopoietic differentiation. Here, we show that endoglin (Eng), a receptor for the TGF␤ superfamily, identifies all cells with hematopoietic fate in the early embryo. These arise in an Eng ؉ Flk1 ؉ mesodermal precursor population at embryonic day 7.5 (E7.5), a cell fraction also endowed with endothelial potential. In Eng-knockout embryos, hematopoietic colony activity and numbers of CD71 ؉ Ter119 ؉ erythroid progenitors were severely reduced. This coincided with severely reduced expression of embryonic globin and key bone morphogenic protein (BMP) target genes, including the hematopoietic regulators Scl, Gata1, Gata2, and Msx-1. To interrogate molecular pathways active in the earliest hematopoietic progenitors, we applied transcriptional profiling to sorted cells from E7. IntroductionDuring mouse development, hematopoiesis occurs at temporally and spatially distinct anatomic sites with the first appearance of hematopoietic cells observed in the blood island (BI) of the extraembryonic yolk sac (YS) at embryonic day 7 (E7.0). 1 This first wave of primitive hematopoiesis produces primitive erythrocytes, megakaryocytes, 2 and macrophages, and is followed by the generation of definitive hematopoietic precursors in the YS at approximately E8.25 days post coitum (dpc). 1 The emergence of hematopoietic stem cells (HSCs) capable of repopulating adult mice is first observed at E10.5 in the aorta-gonad-mesonephros (AGM) region, and later on in other hematopoietic sites, such as YS, placenta, and fetal liver. [3][4][5] HSCs have been proposed to originate from a common precursor for the hematopoietic and endothelial lineages, the hemangioblast, which was initially described using the in vitro embryonic stem cell (ESC) differentiation system, 6 and was later confirmed in the mouse 7 and zebrafish 8 systems. In the murine embryo, this precursor has been identified to be enriched in the primitive streak (PS), and expresses fetal liver kinase 1 (Flk-1 or VEGFR2) in addition to brachyury. Subsequently, these cells migrate to the extraembryonic region, where they give rise to hematopoietic and endothelial cells of the BIs. 7 Endothelial versus hematopoietic fate is thought to be specified en route to the extraembryonic destination because individual BIs are often polyclonal. 9 To date, little is known regarding the molecular and cellular mechanisms involved in the origin and early development of the hematopoietic lineage. It has been reported that signals from extraembryonic ectoderm and visceral endoderm, including fibroblast growth factor 8 (FGF8), WNT3, and hedgehog, are crucial for proper mesoderm patterning, and the latter two are also involved in the specification of the hematopoietic program. 10,11 Members of the TGF␤ superfamily have been shown to play an essential role during vascular development and hematopoiesis. Ligands for the TGF␤ family act through a receptor complex present in the cell surface, which upon phosphorylation causes the ac...

Infantile Hemangioma Originates From A Dysregulated But Not Fully Transformed Multipotent Stem Cell

“…TGF-β signaling is important in normal vascular development (vasculogenesis, angiogenesis, and embryonic vascular assembly) and plays a role in tumor angiogenesis3255565758596061. In early development, endoglin is required for hemangioblast specification, is a marker for an embryonic progenitor, the hemangioblast (in addition to the hemangioblast marker KDR/VEGFR-2/CD309), and serves as an important regulator of hematopoietic and endothelial lineage commitment56575859626364656667. Endoglin expression levels are heterogeneous in different cell sub-populations.…”

TGF-β Family Signaling in Embryonic and Somatic Stem-Cell Renewal and Differentiation

“…BMPs specify the HSC lineage in cooperation with Wnt signaling and the induction of Cdx and Hox gene expression and consequent transcriptional networks (Lengerke et al, 2008). The emergence of the HSC population during gastrulation also requires the TGF-β family accessory receptor, endoglin, which marks all cells of hematopoietic fate and binds both TGF-β and BMP receptor complexes (Barbara et al 1999; Borges et al, 2012). Hematopoietic and endothelial progenitor cells are unusual in that they display strong TGF-β-dependent activation of Smad1 and show elevated expression of endoglin (Oh et al, 2000; Borges et al, 2012), which modulates the magnitude of TGF-β-dependent Smad1 versus Smad2 activation (Pece-Barbara et al, 2005).…”

“…The emergence of the HSC population during gastrulation also requires the TGF-β family accessory receptor, endoglin, which marks all cells of hematopoietic fate and binds both TGF-β and BMP receptor complexes (Barbara et al 1999; Borges et al, 2012). Hematopoietic and endothelial progenitor cells are unusual in that they display strong TGF-β-dependent activation of Smad1 and show elevated expression of endoglin (Oh et al, 2000; Borges et al, 2012), which modulates the magnitude of TGF-β-dependent Smad1 versus Smad2 activation (Pece-Barbara et al, 2005). This may provide a mechanism to balance BMP- versus TGF-β-mediated Smad activation within the HSC niche and provides a key example of how cellular context directs biological outputs in response to TGF-β family signaling (Pece-Barbara et al, 2005).…”

Endoglin: a novel target for therapeutic intervention in acute leukemias revealed in xenograft mouse models

“…[8][9][10] In addition to the endothelial lineage, endoglin also plays a key role in hematopoiesis. We have reported an important function for endoglin in cell fate specification and early hematopoiesis, [11][12][13][14][15] and a potential role beyond the embryonic stage is suggested by the expression of this receptor on the hematopoietic stem cell (HSC) isolated from every hematopoietic site, including the aorta-gonad-mesonephros, 16,17 the fetal liver, 18 and the bone marrow (BM), 19,20 in which endoglin has been reported to identify the long-term repopulating HSC. 18,19,21,22 Transcriptional profiling data of proliferating and quiescent HSCs has demonstrated endoglin to be one of the genes selectively expressed in the quiescent HSC subset.…”