Live imaging of Runx1 expression in the dorsal aorta tracks the emergence of blood progenitors from endothelial cells.
ABSTRACT Blood cells of an adult vertebrate are continuously generated by hematopoietic stem cells (HSCs) that originate during embryonic life within the aorta-gonad-mesonephros region. There is now compelling in vivo evidence that HSCs are generated from aortic endothelial cells and that this process is critically regulated by the transcription factor Runx1. By time-lapse microscopy of Runx1-enhanced green fluorescent protein transgenic zebrafish embryos, we were able to capture a subset of cells within the ventral endothelium of the dorsal aorta, as they acquire hemogenic properties and directly emerge as presumptive HSCs. These nascent hematopoietic cells assume a rounded morphology, transiently occupy the subaortic space, and eventually enter the circulation via the caudal vein. Cell tracing showed that these cells subsequently populated the sites of definitive hematopoiesis (thymus and kidney), consistent with an HSC identity. HSC numbers depended on activity of the transcription factor Runx1, on blood flow, and on proper development of the dorsal aorta (features in common with mammals). This study captures the earliest events of the transition of endothelial cells to a hemogenic endothelium and demonstrates that embryonic hematopoietic progenitors directly differentiate from endothelial cells within a living organism.
- SourceAvailable from: Thierry Jaffredo[Show abstract] [Hide abstract]
ABSTRACT: The chicken embryo has a long history as a key model in developmental biology. Because of its distinctive developmental characteristics, it has contributed to major breakthroughs in the field of hematopoiesis. Among these, the discovery of B lymphocytes and the three rounds of thymus colonization, the embryonic origin of hematopoietic stem cells and the traffic between different hematopoietic organs, the existence of two distinct endothelial cell lineages one angioblastic, restricted to endothelial cells production and another, hemangioblastic, able to produce both endothelial and hematopoietic cells should be cited. The avian model has also contributed to demonstrate the endothelial-to-hematopoietic transition associated with aortic hematopoiesis and the existence of the allantois as a hematopoietic organ. Because the immune system develops relatively late in aves, the avian embryo is used to probe the tissue-forming potential of mouse tissues through mouse-into-chicken chimeras giving insights into early mouse development by circumventing lethality associated with some genetic strains. Finally the avian embryo can be used to investigate the differentiation potential of human ES cells in the context of a whole organism. The combinations of classical approaches with the development of powerful genetic tools make the avian embryo a great and versatile model.Experimental hematology. 07/2014;
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ABSTRACT: Hematopoietic stem cells (HSCs) sustain blood production through life and are of pivotal importance in regenerative medicine. Although HSC generation from pluripotent stem cells would resolve their shortage for clinical applications, this has not yet been achieved mainly due to the poor mechanistic understanding of their programing. Bone marrow HSCs are first created during embryogenesis in the dorsal aorta (DA) of the mid-gestation conceptus, from where they migrate to the fetal liver and, eventually, the bone marrow. It is currently accepted that HSCs emerge from specialised endothelium, the hemogenic endothelium, localised in the ventral wall of the DA through an evolutionarily conserved process called the endothelial to hematopoietic transition (EHT). However, EHT represents one of the last steps in HSC creation and an understanding of earlier events in the specification of their progenitors is required if we are to create them from naïve pluripotent cells. Due to their ready availability and external development, studies on zebrafish and Xenopus embryos have enormously facilitated our understanding of the early developmental processes leading to the programming of HSCs from nascent lateral plate mesoderm to hemogenic endothelium in the DA. The amenity of the Xenopus model to lineage tracing experiments has also contributed to the establishment of the distinct origins of embryonic (yolk sac) and adult (HSC) hematopoiesis, whilst the transparency of the zebrafish has allowed in vivo imaging of developing blood cells, particularly during and after the emergence of HSCs in the DA. Here, we discuss the key contributions of these model organisms to our understanding of developmental hematopoiesis.Experimental hematology. 06/2014;
- Nature 08/2014; · 38.60 Impact Factor