Identification of the niche and phenotype of the first human hematopoietic stem cells

SummaryIn various vertebrate species, the dorsal aorta (Ao) is the site of specification of adult hematopoietic stem cells (HSCs). It has been observed that the upregulation of essential hematopoietic transcription factors and the formation of specific intra-aortic hematopoietic cell clusters occur predominantly in the ventral domain of the Ao (AoV). In the mouse, the first HSCs emerge in the AoV. Here, we demonstrate that in the human embryo the first definitive HSCs also emerge asymmetrically and are localized to the AoV, which thus identifies a functional niche for developing human HSCs. Using magnetic cell separation and xenotransplantations, we show that the first human HSCs are CD34+VE-cadherin+CD45+C-KIT+THY-1+Endoglin+RUNX1+CD38−/loCD45RA−. This population harbors practically all committed hematopoietic progenitors and is underrepresented in the dorsal domain of the Ao (AoD) and urogenital ridges (UGRs). The present study provides a foundation for analysis of molecular mechanisms underpinning embryonic specification of human HSCs

Spatiotemporal dynamics in a spatial plankton system

In this paper, we investigate the complex dynamics of a spatial plankton-fish system with Holling type III functional responses. We have carried out the analytical study for both one and two dimensional system in details and found out a condition for diffusive instability of a locally stable equilibrium. Furthermore, we present a theoretical analysis of processes of pattern formation that involves organism distribution and their interaction of spatially distributed population with local diffusion. The results of numerical simulations reveal that, on increasing the value of the fish predation rates, the sequences spots $\rightarrow$ spot-stripe mixtures$\rightarrow$ stripes$\rightarrow$ hole-stripe mixtures holes$\rightarrow$ wave pattern is observed. Our study shows that the spatially extended model system has not only more complex dynamic patterns in the space, but also has spiral waves.Comment: Published Pape

Highly potent human hematopoietic stem cells first emerge in the intraembryonic aorta-gonad-mesonephros region

Human HSCs appear first in the embryonic dorsal aorta, and only later in the yolk sac, liver, and placenta; a single human AGM region HSC can generate at least 300 daughter HSCs that are retransplantable into secondary recipient mice

Concealed expansion of immature precursors underpins acute burst of adult HSC activity in foetal liver

One day prior to mass emergence of haematopoietic stem cells (HSCs) in the foetal liver at E12.5, the embryo contains only a few definitive HSCs. It is thought that the burst of HSC activity in the foetal liver is underpinned by rapid maturation of immature embryonic precursors of definitive HSCs, termed pre-HSCs. However, because pre-HSCs are not detectable by direct transplantations into adult irradiated recipients, the size and growth of this population, which represents the embryonic rudiment of the adult haematopoietic system, remains uncertain. Using a novel quantitative assay, we demonstrate that from E9.5 the pre-HSC pool undergoes dramatic growth in the aorta-gonad-mesonephros region and by E11.5 reaches the size that matches the number of definitive HSCs in the E12.5 foetal liver. Thus, this study provides for the first time a quantitative basis for our understanding of how the large population of definitive HSCs emerges in the foetal liver

Definitive hematopoiesis is autonomously initiated by the AGM region

AbstractThe adult hematopoietic system of mammals is a dynamic hierarchy of cells with the hematopoietic stem cell at its foundation. During embryonic development, the source and expansion potential of this cell remain unclear. Two sites of hematopoietic activity, the yolk sac and aorta–gonad–mesonephros (AGM) region, function in mouse ontogeny at the pre-liver stage of hematopoiesis. However, cellular interchange between these tissues obscures the embryonic site of hematopoietic stem cell generation. Here we present the results of a novel in vitro organ culture system demonstrating that, at day 10 in gestation, hematopoietic stem cells initiate autonomously and exclusively within the AGM region. Furthermore, we provide evidence for the in vitro expansion of hematopoietic stem cells within the AGM region. These results strongly suggest that the AGM region is the source of the definitive adult hematopoietic system, which subsequently colonizes the liver

Hierarchical organization and early hematopoietic specification of the developing HSC lineage in the AGM region

A CD45-negative population of pre-HSCs develops into definitive HSCs in the AGM region of the embryo

Development of hematopoietic stem cell activity in the mouse embryo.

The precise time of appearance of the first hematopoietic stem cell activity in the developing mouse embryo is unknown. Recently the aorta-gonad-mesonephros region of the developing mouse embryo has been shown to possess hematopoietic colony-forming activity (CFU-S) in irradiated recipient mice. To determine whether the mouse embryo possesses definitive hematopoietic stem cell activity in the analogous AGM region and to determine the order of appearance of stem cells in the yolk sac, AGM region, and liver, we transferred these embryonic tissues into adult irradiated recipients. We report here the long-term, complete, and functional hematopoietic repopulation of primary and serial recipients with AGM-derived cells. We observe potent hematopoietic stem cell activity in the AGM region before the appearance of yolk sac and liver stem cell activity and discuss a model for the maturation of stem cell activity in mouse embryogenesis