A common precursor for primitive erythropoiesis and definitive haematopoiesis

Abstract

The generation of blood cells, haematopoiesis, in the mouse embryo begins with the development of primitive nucleated erythroid cells in the yolk sac followed by the appearance of precursors for multiple definitive haematopoietic lineages. The later developing lineages arise from multipotential stem cells, but the relationship of primitive erythroid cells to these other haematopoietic populations is unknown. Using an in vitro embryonic stem (ES) cell differentiation system, we show that primitive erythrocytes and other haematopoietic lineages arise from a common multipotential precursor that develops within embryoid bodies generated from differentiated ES cells. In response to vascular endothelial growth factor and c-kit ligand these precursors give rise to colonies containing immature cells (blasts) expressing marker genes characteristic of haematopoietic precursors. Many blast colonies also expressed betaH1 and beta major globins but not Brachyury, a mesodermal marker. Kinetic analysis demonstrated that the blast colony-forming cells represent a transient population, preceding the establishment of the primitive erythroid and other lineage-restricted precursors. This precursor population may represent the earliest stage of embryonic haematopoietic commitment.

Yolk-sac hematopoiesis

“…Day-5 CFU-E progenitors arose early on the eighth gestational day exclusively in the yolk sac and disappeared by E9 [40]. It was subsequently confirmed that day 5 CFU-E are primitive erythroid progenitors (EryP-CFC) that generate colonies in semisolid media with a distinct timing of differentiation, morphology, and pattern of gene expression compared to the definitive BFU-E and CFU-E [41]. EryP-CFC generate colonies comprised of large nucleated primitive erythroid cells that express both embryonic and adult globins.…”

Roles of TGF-β family signaling in stem cell renewal and differentiation

“…Initial differentiation of hematopoietic cells and vascular endothelium during mouse embryogenesis occurs in the mesodermal layer of the yolk sac, yielding structures named blood islands, which consist of common progenitors for embryonic blood and blood vessels. These progenitors express Flk1 and are called hemangioblasts [33,34] (Figure 2). Importantly, differentiated ES cells contain a significant proportion of Flk1-positive (Flk1 + ) hematopoietic-endothelial progenitor cells when cultured under optimized conditions [33][34][35][36].…”

“…These progenitors express Flk1 and are called hemangioblasts [33,34] (Figure 2). Importantly, differentiated ES cells contain a significant proportion of Flk1-positive (Flk1 + ) hematopoietic-endothelial progenitor cells when cultured under optimized conditions [33][34][35][36]. Park et al [31].…”

Molecular and developmental biology of the hemangioblast

“…Searching for the hemangioblast is partly inspired by previous studies in chick (Sabin, 1920;Eichmann et al, 1997). Choi and colleagues pioneered to establish the classic blast colony assay using the mouse ESC/EB system and discovered the BL-CFCs that could clonally give rise to both endothelial and hematopoietic cells in the presence of appropriate cytokines such as VEGF (Kennedy et al, 1997;Choi et al, 1998). Therefore, the BL-CFC is considered as the in vitro equivalent of the hemangioblast proposed by Sabin in 1920.…”