Identification of novel regulators of developmental hematopoiesis using Endoglin regulatory elements as molecular probes

Nasrallah, Rabab; Fast, Eva M.; Solaimani, Parham; Knezevic, Kathy; Eliades, Alexia; Patel, Rahima; Thambyrajah, Roshana; Unnikrishnan, Ashwin; Thoms, Julie A.I.; Beck, Dominik; Vink, Chris S.; Smith, Adam; Wong, Jason; Shepherd, Mairi; Kent, David G.; Roychoudhuri, Rahul; Paul, Fabian; Klippert, Julia; Hammes, Annette; Willnow, Thomas E.; Göttgens, Berthold; Dzierzak, Elaine; Zon, Leonard I.; Lacaud, Georges; Kouskoff, Valérie; Pimanda, John E.

doi:10.1182/blood-2016-02-697870

Cited by 7 publications

(6 citation statements)

References 55 publications

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“…The existence of two haematogenic precursors that are broadly equivalent in their ability to produce haematopoietic lineages suggests that there are multiple cellular pathways to blood production in the yolk sac, one endothelial affiliated (haemangioblast) and one mesenchymal affiliated (haematomesoblast). The unequivocal role of transcriptional master regulators such as GATA1, GATA2, RUNX1, and TAL1 for in vivo blood cell emergence 8,19,21,32,33,[51][52][53][54][55][56][57][58][59][60][61][62][63] , and that E10.5 differentiated lineages cluster homogeneously, is consistent with the notion that haemangioblast and haematomesoblast differentiation routes must converge on the same molecular machinery to induce haematopoietic commitment. This likely occurs at the level of the E7.25-E7.75 Cdh5 + haemato-endothelial precursors, which might have the capacity for Haem group or endothelial lineage production but do not generally contribute to both outcomes.…”

Section: Discussionsupporting

confidence: 75%

In vivo clonal tracking reveals evidence of haemangioblast and haematomesoblast contribution to yolk sac haematopoiesis

et al. 2023

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During embryogenesis, haematopoietic and endothelial lineages emerge closely in time and space. It is thought that the first blood and endothelium derive from a common clonal ancestor, the haemangioblast. However, investigation of candidate haemangioblasts in vitro revealed the capacity for mesenchymal differentiation, a feature more compatible with an earlier mesodermal precursor. To date, no evidence for an in vivo haemangioblast has been discovered. Using single cell RNA-Sequencing and in vivo cellular barcoding, we have unravelled the ancestral relationships that give rise to the haematopoietic lineages of the yolk sac, the endothelium, and the mesenchyme. We show that the mesodermal derivatives of the yolk sac are produced by three distinct precursors with dual-lineage outcomes: the haemangioblast, the mesenchymoangioblast, and a previously undescribed cell type: the haematomesoblast. Between E5.5 and E7.5, this trio of precursors seeds haematopoietic, endothelial, and mesenchymal trajectories.

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Section: Discussionsupporting

confidence: 75%

In vivo clonal tracking reveals evidence of haemangioblast and haematomesoblast contribution to yolk sac haematopoiesis

et al. 2023

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“…This cell population was also found to express hematoendothelial markers Cdh5, Icam2, Cd40, confirming the bipotent nature of these cells (45)(46)(47). As a high expression of the arterial-specific marker Delta-like, 4 (Dll4) is essential for the segregation of the endothelial lineage from the hematopoietic lineage (48,49), we looked at the Dll4 expression in this subset, and found that this cluster expresses a high level of Dll4.…”

Section: Loss Of Gata Factors Disrupts Hematopoietic-endothelial Cellmentioning

confidence: 60%

Trophoblast paracrine signaling regulates placental hematoendothelial niche

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Ghosh

Kumar

et al. 2019

Preprint

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The placenta acts as a major organ for hematopoiesis. It is believed that placental hematopoietic stem and progenitor cells (HSPCs) migrate to the fetal liver to ensure optimum hematopoiesis in the developing embryo. The labyrinth vasculature in a mid-gestation mouse placenta provides a niche for the definitive hematopoietic stem cell (HSC) generation and expansion. It has been proposed that these processes are regulated by a host of paracrine factors secreted by trophoblast giant cells (TGCs) at the maternal-fetal interface. However, the molecular mechanism by which the TGCs regulate the hematoendothelial niche in a developing placenta is yet to be defined. Using a TGC-specific Gata2 and Gata3 double knockout mouse model, weshow that the loss of GATA2 and GATA3 at the TGC layer leads to fetal growth retardation and embryonic death due to disruptions in the delicate hematopoietic-angiogenic balance in the developing placenta. Using single-cell RNA-Seq analyses, we also show that the loss of GATA factors in the TGCs results in the loss of HSC population within the placental labyrinth and is associated with defective placental angiogenesis. Interestingly, we also found that this TGCspecific GATA factor-loss leads to impaired differentiation and distribution of trophoblast progenitor cells. Our study helps to define the GATA-dependent non-autonomous signaling mechanisms of the primary parietal trophoblast giant cells by which it regulates the delicate hematopoietic-angiogenic balance in the developing placenta.

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“…Interpretation of the phenotype of Tie2-Cre; Lrp2 flx/flx mice is confounded by the activity of the driver line in endothelial cells of all tissues, endocardial cells, and the hematopoietic cell line. Lrp2 is expressed in endocardial cells, myeloid cells, in developing endothelial cells, and is involved in hematopoiesis [ 43 , 44 , 45 ], suggesting that the phenotype of Tie2-Cre; Lrp2 flx/flx mice may be due to effects generated outside of the BBB.…”

Section: Discussionmentioning

confidence: 99%

Is LRP2 Involved in Leptin Transport over the Blood-Brain Barrier and Development of Obesity?

Sandin

Folberth

Müller-Fielitz

et al. 2021

IJMS

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The mechanisms underlying the transport of leptin into the brain are still largely unclear. While the leptin receptor has been implicated in the transport process, recent evidence has suggested an additional role of LRP2 (megalin). To evaluate the function of LRP2 for leptin transport across the blood-brain barrier (BBB), we developed a novel leptin-luciferase fusion protein (pLG), which stimulated leptin signaling and was transported in an in vitro BBB model based on porcine endothelial cells. The LRP inhibitor RAP did not affect leptin transport, arguing against a role of LRP2. In line with this, the selective deletion of LRP2 in brain endothelial cells and epithelial cells of the choroid plexus did not influence bodyweight, body composition, food intake, or energy expenditure of mice. These findings suggest that LRP2 at the BBB is not involved in the transport of leptin into the brain, nor in the development of obesity as has previously been described.

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Identification of novel regulators of developmental hematopoiesis using Endoglin regulatory elements as molecular probes

Abstract: Key Points ENG regulatory elements target hemogenic mesoderm and hemogenic endothelium. Hemogenic progenitors can be enriched using these elements as molecular probes to discover novel regulators of hematopoiesis.

Cited by 7 publications

References 55 publications

In vivo clonal tracking reveals evidence of haemangioblast and haematomesoblast contribution to yolk sac haematopoiesis

In vivo clonal tracking reveals evidence of haemangioblast and haematomesoblast contribution to yolk sac haematopoiesis

Trophoblast paracrine signaling regulates placental hematoendothelial niche

Is LRP2 Involved in Leptin Transport over the Blood-Brain Barrier and Development of Obesity?

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