Modulation of TGF-β signaling by endoglin in murine hemangioblast development and primitive hematopoiesis

Zhang, Liying; Magli, Alessandro; Catanese, Jacquelyn; Xu, Zhaohui; Kyba, Michael; Perlingeiro, Rita C.R.

doi:10.1182/blood-2010-12-325019

Cited by 40 publications

(71 citation statements)

References 53 publications

(71 reference statements)

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“…This was corroborated by the significantly lower levels of pSMAD1/5/8 and downstream targets of BMP4 observed previously in differentiating, Engdeficient ESCs. 55 The results of the present study demonstrate that Eng is required for proper hematopoietic development and that virtually all YS hematopoiesis is restricted to the Eng ϩ cell fraction. This progenitor population responds to BMP4, BMP2, and TGF␤1.…”

Section: Discussionmentioning

confidence: 49%

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

Borges¹,

Iacovino

Mayerhofer³

et al. 2012

Blood

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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...

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Section: Discussionmentioning

confidence: 49%

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

Borges¹,

Iacovino

Mayerhofer³

et al. 2012

Blood

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“…showed that these receptors are important for hemangioblast development and primitive hematopoiesis. 44 Recently, Ldb1 has been implicated in cell migration and focal adhesion through an interaction with the Ste20-like kinase (SLK), a microtubuleassociated protein necessary for migration. 45 Our data show that expression of a number of focal adhesion proteins is affected, although SLK did not appear to change.…”

Section: Discussionmentioning

confidence: 99%

Genome-wide analysis shows that Ldb1 controls essential hematopoietic genes/pathways in mouse early development and reveals novel players in hematopoiesis

Mylona

Andrieu-Soler

Thongjuea

et al. 2013

Blood

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“…[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.…”

Section: Introductionmentioning

confidence: 99%

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

Dourado

Baik

Oliveira

et al. 2017

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• Leukemia-forming activity is enriched in endoglinexpressing AML and B-ALL blasts using a mouse xenograft model. • Inhibition of endoglin function with TRC105 reduces leukemia development and progression.Endoglin (CD105), a receptor of the transforming growth factor-b superfamily, has been reported to identify functional long-term repopulating hematopoietic stem cells, and has been detected in certain subtypes of acute leukemias. Whether this receptor plays a functional role in leukemogenesis remains unknown. We identified endoglin expression on the majority of blasts from patients with acute myeloid leukemia (AML) and acute B-lymphoblastic leukemia (B-ALL). Using a xenograft model, we find that CD105 1 blasts are endowed with superior leukemogenic activity compared with the CD105 2 population.We test the effect of targeting this receptor using the monoclonal antibody TRC105, and find that in AML, TRC105 prevented the engraftment of primary AML blasts and inhibited leukemia progression following disease establishment, but in B-ALL, TRC105 alone was ineffective due to the shedding of soluble CD105. However, in both B-ALL and AML, TRC105 synergized with reduced intensity myeloablation to inhibit leukemogenesis, indicating that TRC105 may represent a novel therapeutic option for B-ALL and AML. (Blood. 2017;129(18):2526-2536

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Modulation of TGF-β signaling by endoglin in murine hemangioblast development and primitive hematopoiesis

Cited by 40 publications

References 53 publications

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

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

Genome-wide analysis shows that Ldb1 controls essential hematopoietic genes/pathways in mouse early development and reveals novel players in hematopoiesis

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

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