Primitive erythropoiesis in the mammalian embryo

Abstract

Erythropoiesis in adult mammals is characterized by the progressive maturation of hematopoietic stem cells to lineage-specific progenitors, to morphologically identifiable precursors which enucleate to form mature erythrocytes. In contrast, primitive erythropoiesis is characterized by the appearance within the yolk sac of a transient, lineage-restricted progenitor population which generates a wave of erythroid precursors. These precursors undergo progressive maturation in the bloodstream, characterized by nuclear condensation and embryonic hemoglobin accumulation. This process is dependent on erythropoietin signaling through its cognate receptor, as well as the function of several erythroid-specific transcription factors, including GATA1 and EKLF. Targeted disruption of genes in the mouse that result in failure of the emergence or maturation of the primitive erythroid lineage leads to early fetal death, indicating that the primitive erythroid lineage is necessary for survival of the mammalian embryo. While it was thought for over a century that primitive erythroid cells were uniquely nucleated mammalian red cells, it is now recognized that they, like their definitive erythroid counterparts, enucleate to form reticulocytes and pyrenocytes. This surprising finding indicates that the primitive erythroid lineage is indeed mammalian, rather than non-mammalian, in character.

Identification of Biologically Relevant Enhancers in Human Erythroid Cells

“…Mammalian erythroid cells originate from hematopoietic stem and progenitor cells. In the embryo and fetus, erythroid cells have differing developmental origins, with the primitive erythroid cell lineage developing from yolk sac-derived erythroid progenitors and the definitive cell lineage maturing from two different developmentally regulated stem and progenitor cell populations (67)(68)(69)(70). These cells have different programs of regulation, with variation in spatial, temporal, and site-specific differentiation.…”

From stem cell to red cell: regulation of erythropoiesis at multiple levels by multiple proteins, RNAs, and chromatin modifications

“…62 Importantly, enucleation is not restricted to definitive erythroid cells; primitive yolk-sac derived erythropoiesis also exhibits chromatin condensation and enucleation. 63 While nuclear condensation is thought to be critical for mammalian enucleation, chromatin condensation also occurs in many other tissue types, including rather ubiquitous cellular processes, such as cell division and apoptosis. Apoptotic mechanisms, such as caspase activation, are known to be responsible for enucleation of lens epithelia and keratinocytes, although the process is not similar to enucleation of erythroid precursors.…”

Erythropoietin and Cardiovascular System

“…8 Although possible EPO production in renal tubular cells was reported previously 9, 10 a more recent study has shown that fibroblast-like cells in the corticomedullary interstitium of the kidney synthesize EPO, while tubular cells do not. 8 Proliferative effect of EPO on several progenitor cells including erythroid progenitor cells, [11][12][13] endothelial progenitor cells (EPC), 14,15 cardiomyogenic stem cells 37 has been reported. EPO is known to act specifically on haematopoietical cells, however recent evidence demonstrated several non-haematopoietical effects.…”

“…40 During embryo development, immature primitive erythroblasts begin to enter the bloodstream with the onset of cardiac contractions. 11 Ji et al 41 hypothesized that the timing of onset of heartbeat and erythroid cell migration are tightly coordinated.…”

“…In vitro and in vivo studies suggested that EPO may have a role in expansion of the progenitor pool, with or without other growth factors. 11,12 Exogenous erythropoietin abrogates apoptosis of immature primitive erythroid cells cultured in vitro. 13 EPO promotes endothelial progenitor cells (EPC) proliferative and adhesive properties.…”