Ventral embryonic tissues and Hedgehog proteins induce early AGM hematopoietic stem cell development

Peeters, Maria C. W.; Ottersbach, Katrin; Bollérot, Karine; Orelio, Claudia; Bruijn, Marella de; Wijgerde, Mark; Dzierzak, Elaine

doi:10.1242/dev.034728

Cited by 98 publications

(93 citation statements)

References 51 publications

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“…Apart from structural endothelial cells, the budding hematopoietic cells are in close vicinity of vascular smooth muscle cells and peri-vascular mesenchyme, the latter extending into the gut mesentery [74] (Figure 2a). Interestingly, there is extensive Runx1 expression in the abluminal cell layers of the dorsal aorta ( [36]; Figure 2b).…”

Section: The Microenvironment Supporting Ehtmentioning

confidence: 99%

A short history of hemogenic endothelium

Swiers

Rode

Azzoni

et al. 2013

Blood Cells, Molecules, and Diseases

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Definitive hematopoietic cells are generated de novo during ontogeny from a specialized subset of endothelium, the so-called hemogenic endothelium. In this review we give a brief overview of the identification of hemogenic endothelium, explore its links with the HSC lineage, and summarize recent insights into the nature of hemogenic endothelium and the microenvironmental and intrinsic regulators contributing to its transition into blood. Ultimately, a better understanding of the processes controlling the transition of endothelium into blood will advance the generation and expansion of hematopoietic stem cells for therapeutic purposes.

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Section: The Microenvironment Supporting Ehtmentioning

confidence: 99%

A short history of hemogenic endothelium

Swiers

Rode

Azzoni

et al. 2013

Blood Cells, Molecules, and Diseases

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“…This suggests that the ventral region of the dorsal aorta contains exclusive signals that are capable of inducing and expanding definitive HSCs. One ventral signaling pathway, which predominantly acts at early E10 and arises from the developing gut, is the Hedgehog pathway [54]. AGM:gut explants from early E10 embryos contain HSCs after 3 days in culture.…”

Section: Signals From Cells In the Gutmentioning

confidence: 99%

Concise Review: From Greenhouse to Garden: The Changing Soil of the Hematopoietic Stem Cell Microenvironment During Development

2014

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The hematopoietic system has been intensely studied for many decades. For this reason, it has become the best understood stem cell-derived system that serves as a paradigm for stem cell biology and has found numerous applications in the clinics. While a lot of progress has recently been made in describing the bone marrow components that maintain and control blood stem cell function in the adult, very little is currently known about the regulatory microenvironment in which the first adult-repopulating hematopoietic stem cells are formed during development. Knowledge of these processes is crucial for understanding the basic regulation of hematopoietic stem cell production and behavior and to allow their in vitro expansion and generation from embryonic stem cells or iPS cells for clinical and research purposes. This review summarizes the recent advances that have been made in defining the cellular components, as well as the soluble and physical factors, that are part of the niche involved in regulating hematopoietic stem cell generation in the embryo. The findings are compared with what is known about the adult bone marrow niche to find common pathways for stem cell regulation, but also to highlight processes uniquely required for de novo hematopoietic stem cell generation, as these are the conditions that will need to be recreated for the successful production of blood stem cells in culture.

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“…25,26 Furthermore, signals emanating from the gut, where Dlk1 is expressed at high levels, have been shown to be important for HSC production. 27 This implies that Dlk1 may also be involved in the regulation of HSCs in the AGM. The transcription factor Runx1 is essential for HSC emergence in the AGM and is expressed in the ventral endothelium of the aorta, the ventral para-aortic mesenchyme and intraaortic hematopoietic clusters at E11 (Figure 2A).…”

Section: Dlk1 Expression Is Dependent On the Transcription Factor Runx1mentioning

confidence: 99%

Dlk1 is a negative regulator of emerging hematopoietic stem and progenitor cells

Mirshekar-Syahkal

Haak²,

Kimber

et al. 2012

Haematologica

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The first mouse adult-repopulating hematopoietic stem cells emerge in the aorta-gonad-mesonephros region at embryonic day (E) 10.5. Their numbers in this region increase thereafter and begin to decline at E12.5, thus pointing to the possible existence of both positive and negative regulators of emerging hematopoietic stem cells. Our recent expression analysis of the aorta-gonad-mesonephros region showed that the Delta-like homologue 1 (Dlk1) gene is up-regulated in the region of the aorta-gonad-mesonephros where hematopoietic stem cells are preferentially located. To analyze its function, we studied Dlk1 expression in wild-type and hematopoietic stem cell-deficient embryos and determined hematopoietic stem and progenitor cell activity in Dlk1 knockout and overexpressing mice. Its role in hematopoietic support was studied in co-culture experiments using stromal cell lines that express varying levels of Dlk1. We show here that Dlk1 is expressed in the smooth muscle layer of the dorsal aorta and the ventral sub-aortic mesenchyme, where its expression is dependent on the hematopoietic transcription factor Runx1. We further demonstrate that Dlk1 has a negative impact on hematopoietic stem and progenitor cell activity in the aorta-gonad-mesonephros region in vivo, which is recapitulated in co-cultures of hematopoietic stem cells on stromal cells that express varying levels of Dlk1. This negative effect of Dlk1 on hematopoietic stem and progenitor cell activity requires the membrane-bound form of the protein and cannot be recapitulated by soluble Dlk1. Together, these data suggest that Dlk1 expression by cells of the aorta-gonad-mesonephros hematopoietic microenvironment limits hematopoietic stem cell expansion and is, to our knowledge, the first description of such a negative regulator in this tissue.

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Ventral embryonic tissues and Hedgehog proteins induce early AGM hematopoietic stem cell development

Cited by 98 publications

References 51 publications

A short history of hemogenic endothelium

A short history of hemogenic endothelium

Concise Review: From Greenhouse to Garden: The Changing Soil of the Hematopoietic Stem Cell Microenvironment During Development

Dlk1 is a negative regulator of emerging hematopoietic stem and progenitor cells

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