The TGFβ pathway is a key player for the endothelial-to-hematopoietic transition in the embryonic aorta

Lempereur, Aveline; Canto, Pierre-Yves; Richard, Charlotte; Martín, Sabrina; Thalgott, Jérémy H.; Raymond, Karine; Lebrin, Franck; Drevon, C.; Jaffredo, Thierry

doi:10.1016/j.ydbio.2017.12.006

Cited by 12 publications

(20 citation statements)

References 67 publications

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“…Once these precursors incorporate into the nascent dorsal aorta, their transition to HSPCs is instructed via HSPCs. Previous work has suggested that the mesenchyme, located directly underneath the dorsal aorta, is a source of BMP ligand necessary for the HSC emergence (Crisan et al, 2015;Durand et al, 2007;Lempereur et al, 2018;Pouget et al, 2014;Wilkinson et al, 2009). More recent studies have also elucidated a role for non-hemogenic ECs in supporting the hemogenic program and in amplifying HSPC number Butler et al, 2010;Gori et al, 2015;Gori et al, 2017;Guo et al, 2017;Hadland et al, 2015;Kim et al, 2014;Kobayashi et al, 2010;Lis et al, 2017;Raynaud et al, 2013;Sandler et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

Dermomyotome-derived endothelial cells migrate to the dorsal aorta to support hematopoietic stem cell emergence

Traver

Sahai

Pouget

et al. 2020

Preprint

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Development of the dorsal aorta is a key step in the establishment of the adult bloodforming system, since hematopoietic stem and progenitor cells (HSPCs) arise from ventral aortic endothelium in all vertebrate animals studied. Work in zebrafish has demonstrated that arterial and venous endothelial precursors arise from distinct subsets of lateral plate mesoderm. Earlier studies in the chick showed that paraxial mesoderm generates another subset of endothelial cells that incorporate into the dorsal aorta to replace HSPCs as they exit the aorta and enter circulation. Here we show that a similar process occurs in the zebrafish, where a population of endothelial precursors delaminates from the somitic dermomyotome to incorporate exclusively into the developing dorsal aorta. Whereas somite-derived endothelial cells (SDECs) lack hematopoietic potential, they act as local niche to support the emergence of HSPCs from neighboring hemogenic endothelium. Thus, at least three subsets of endothelial cells (ECs) contribute to the developing dorsal aorta: vascular ECs, hemogenic ECs, and SDECs. Taken together, our findings indicate that the distinct spatial origins of endothelial precursors dictate different cellular potentials within the developing dorsal aorta.

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Section: Discussionmentioning

confidence: 99%

Dermomyotome-derived endothelial cells migrate to the dorsal aorta to support hematopoietic stem cell emergence

Traver

Sahai

Pouget

et al. 2020

Preprint

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“…Activation of the Tgfb pathway was shown to promote the EMT, while its role in the EHT has been seemingly controversial. While some reports suggested that activation of Tgfb signalling promotes the EHT [81,82], others suggested that Tgfb activity needs to be down-regulated for the EHT to proceed [37,80,83]. While some of the controversies may be explained by the suggestion that the compound SB431542, commonly employed as an inhibitor of the Tgfb pathway [37,83], may have a more complex mode of action and can in fact increase phosphorylation and activation of Smad2/3 [82], which are downstream effectors of Tgfb signalling, other reports suggest that Tgfb signalling, like Notch activation, is essential for the specification of HECs, but may have to be down-regulated for the EHT to proceed [80].…”

Section: Eht Vs Epithelial-to-mesenchymal Transitionmentioning

confidence: 99%

Endothelial-to-haematopoietic transition: an update on the process of making blood

Ottersbach

2019

Biochemical Society Transactions

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The first definitive blood cells during embryogenesis are derived from endothelial cells in a highly conserved process known as endothelial-to-haematopoietic transition (EHT). This conversion involves activation of a haematopoietic transcriptional programme in a subset of endothelial cells in the major vasculature of the embryo, followed by major morphological changes that result in transitioning cells rounding up, breaking the tight junctions to neighbouring endothelial cells and adopting a haematopoietic fate. The whole process is co-ordinated by a complex interplay of key transcription factors and signalling pathways, with additional input from surrounding tissues. Diverse model systems, including mouse, chick and zebrafish embryos as well as differentiation of pluripotent cells in vitro, have contributed to the elucidation of the details of the EHT, which was greatly accelerated in recent years by sophisticated live imaging techniques and advances in transcriptional profiling, such as single-cell RNA-Seq. A detailed knowledge of these developmental events is required in order to be able to apply it to the generation of haematopoietic stem cells from pluripotent stem cells in vitro — an achievement which is of obvious clinical importance. The aim of this review is to summarise the latest findings and describe how these may have contributed towards achieving this goal.

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“…In addition, a number of studies have demonstrated that the NOTCH signaling pathway promotes EHT by activating HES1 both in vitro and in vivo [10][11][12][13][14]. In contrast, TGFβ signaling exerts a negative effect during EHT [15][16][17][18]. Elevated expression of TGFβ signaling components has been identified in endothelial cells and decreased during EHT in mouse embryos [15].…”

Section: Introductionmentioning

confidence: 99%

“…In contrast, TGFβ signaling exerts a negative effect during EHT [15][16][17][18]. Elevated expression of TGFβ signaling components has been identified in endothelial cells and decreased during EHT in mouse embryos [15]. Activation of TGFβ signaling completely abolishes the generation of HPCs from HEPs, while TGFβ inhibition promotes the transition-a response conserved in both mouse and human embryonic stem cells [15][16][17][18].…”

Section: Introductionmentioning

confidence: 99%

“…Elevated expression of TGFβ signaling components has been identified in endothelial cells and decreased during EHT in mouse embryos [15]. Activation of TGFβ signaling completely abolishes the generation of HPCs from HEPs, while TGFβ inhibition promotes the transition-a response conserved in both mouse and human embryonic stem cells [15][16][17][18]. Despite its well documented vital role in EHT, little is known about how TGFβ signaling exerts its function during this process.…”

Section: Introductionmentioning

confidence: 99%

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MSX2 suppression through inhibition of TGFβ signaling enhances hematopoietic differentiation of human embryonic stem cells

Wang

et al. 2020

Stem Cell Res Ther

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Background: Strategies of generating functional blood cells from human pluripotent stem cells (hPSCs) remain largely unsuccessful due to the lack of a comprehensive understanding of hematopoietic development. Endothelialto-hematopoietic transition (EHT) serves as the pivotal mechanism for the onset of hematopoiesis and is negatively regulated by TGF-β signaling. However, little is known about the underlying details of TGF-β signaling during EHT. Methods: In this study, by applying genome-wide gene profiling, we identified muscle segment homeobox2 (MSX2) as a potential mediator of TGF-β signaling during EHT. We generated MSX2-deleted human embryonic stem cell (hESC) lines using the CRISPR/Cas9 technology and induced them to undergo hematopoietic differentiation. The role of MSX2 in hematopoiesis and functional regulation of TGFβ signaling in EHT was studied. Results: We identified MSX2 as a novel regulator of human hematopoiesis. MSX2 deletion promotes the production of hematopoietic cells from hESCs. Functional and bioinformatics studies further demonstrated that MSX2 deletion augments hematopoietic differentiation of hESCs by facilitating EHT. Mechanistically, MSX2 acts as a downstream target of TGFβ signaling to mediate its function during EHT. Conclusions: Our results not only improve the understanding of EHT, but may also provide novel insight into the efficient production of functional blood cells from hPSCs for regenerative medicine.

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The TGFβ pathway is a key player for the endothelial-to-hematopoietic transition in the embryonic aorta

Cited by 12 publications

References 67 publications

Dermomyotome-derived endothelial cells migrate to the dorsal aorta to support hematopoietic stem cell emergence

Dermomyotome-derived endothelial cells migrate to the dorsal aorta to support hematopoietic stem cell emergence

Endothelial-to-haematopoietic transition: an update on the process of making blood

MSX2 suppression through inhibition of TGFβ signaling enhances hematopoietic differentiation of human embryonic stem cells

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