Rodolphe Gautier

Somite-derived cells replace ventral aortic hemangioblasts and provide aortic smooth muscle cells of the trunk

We have previously shown that endothelial cells of the aortic floor give rise to hematopoietic cells, revealing the existence of an aortic hemangioblast. It has been proposed that the restriction of hematopoiesis to the aortic floor is based on the existence of two different and complementary endothelial lineages that form the vessel: one originating from the somite would contribute to the roof and sides, another from the splanchnopleura would contribute to the floor. Using quail/chick orthotopic transplantations of paraxial mesoderm, we have traced the distribution of somite-derived endothelial cells during aortic hematopoiesis. We show that the aortic endothelium undergoes two successive waves of remodeling by somitic cells: one when the aortae are still paired, during which the initial roof and sides of the vessels are renewed; and a second, associated to aortic hematopoiesis, in which the hemogenic floor is replaced by somite endothelial cells. This floor thus appears as a temporary structure, spent out and replaced. In addition, the somite contributes to smooth muscle cells of the aorta. In vivo lineage tracing experiments with non-replicative retroviral vectors showed that endothelial cells do not give rise to smooth muscle cells. However, in vitro, purified endothelial cells acquire smooth muscle cells characteristics. Taken together, these data point to the crucial role of the somite in shaping the aorta and also give an explanation for the short life of aortic hematopoiesis.

Aortic remodelling during hemogenesis: is the chicken paradigm unique?

Since the era of the ancient Egyptians and Greeks, the avian embryo has been a subject of intense interest to visualize the first steps of development. It has served as a pioneer model to scrutinize the question of hematopoietic development from the beginning of the 20th century. Its large size and easy accessibility have permitted the development of techniques dedicated to following the origins and fates of different cell populations. Here, we shall review how the avian model has brought major contributions to our understanding of the development of the hematopoietic system in the past four decades and how these discoveries have influenced our knowledge of mammalian hematopoietic development. The discovery of an intra-embryonic source of hematopoietic cells and the developmental link between endothelial cells and hematopoietic cells will be presented. We shall then point to the pivotal role of the somite in the construction of the aorta and hematopoietic production and demonstrate how two somitic compartments cooperate to construct the definitive aorta. We shall finish by showing how fate-mapping experiments have allowed the identification of the tissue which gives rise to the sub-aortic mesenchyme. Taken together, this review aims to give an overview of how and to what extent the avian embryo has contributed to our knowledge of developmental hematopoiesis.

Endoglin expression level discriminates long-term hematopoietic from short-term clonogenic progenitor cells in the aorta

CD105 is an auxiliary receptor for the transforming growth factor beta superfamily, highly expressed on proliferating endothelial cells and adult hematopoietic stem cells. Because CD105 mRNA expression was reported in the developing aortic region, we further characterized its expression profile in the aorta and examined the hematopoietic potential of CD105+ cells. Aortic endothelial cells, intra-aortic hematopoietic cell clusters and the purified cell fraction enriched in progenitor/hematopoietic stem cell activity expressed CD105. Aortic hematopoietic short-term clonogenic progenitors were highly enriched in the CD105intermediate population whereas more immature long-term progenitors/hematopoietic stem cells are contained within the CD105high population. This places CD105 on the short list of molecules discriminating short-term versus long-term progenitors in the aorta. Furthermore, decreasing transforming growth factor beta signaling increases the number of clonogenic progenitors. This suggests that CD105 expression level defines a hierarchy among aortic hematopoietic cells allowing purification of clonogenic versus more immature hematopoietic progenitors, and that the transforming growth factor beta pathway plays a critical role in this process.

Avian HSC emergence, migration, and commitment toward the T cell lineage

To date three sites of emergence of hemopoietin cells have been identified during early avian development: the yolk sac, the intraaortic clusters and recently the allantois. However, the contributions of the hematopoietic stem cell (HSC) populations generated by these different sites to definitive hematopoiesis and their migration routes are not fully unraveled. Experimental embryology as well as the establishment of the genetic cascades involved in HSC emergence help now to draw a better scheme of these processes.

Extra- and Intraembryonic HSC Commitment in the Avian Model

Hematopoietic stem cells (HSC) are at the basis of the hematopoietic system construction. In adult higher Vertebrates, HSC, defined by their multipotentiality and self-renewal capacity, setde in the bone marrow where they can differentiate into progenitors with more restricted lineage potential and generate all blood lineages via a cascade of commitment events. However HSC are generated during the earliest phases of embryonic development into specific sites. Genetic technologies in the mouse have revealed a number of mutations that affect the production of blood cells, some of which early during development. The tiny mouse embryo embedded in the uterus is not however the most appropriate model to study the earliest events of the development for the analysis of cell commitment, cell migration and cell interaction. Work in the avian embryo has led to several breakthroughs in analysing the ontogeny of the hematopoietic system. Here we will review the main steps that have paved a 30 year analysis of the construction of the hematopoietic system.