Erythropoiesis in the Absence of Adult Hemoglobin (original) (raw)
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Blood, 2011
A transient erythromyeloid wave of definitive hematopoietic progenitors (erythroid/myeloid progenitors [EMPs]) emerges in the yolk sac beginning at embryonic day 8.25 (E8.25) and colonizes the liver by E10.5, before adult-repopulating hematopoietic stem cells. At E11.5, we observe all maturational stages of erythroid precursors in the liver and the first definitive erythrocytes in the circulation. These early fetal liver erythroblasts express predominantly adult β-globins and the definitive erythroid-specific transcriptional modifiers c-myb, Sox6, and Bcl11A. Surprisingly, they also express low levels of “embryonic” βH1-, but not εy-, globin transcripts. Consistent with these results, RNA polymerase and highly modified histones are found associated with βH1- and adult globin, but not εy-globin, genes. E11.5 definitive proerythroblasts from mice transgenic for the human β-globin locus, like human fetal erythroblasts, express predominately human γ-, low β-, and no ε-globin transcripts...
Erythropoiesis: Model systems, molecular regulators, and developmental programs
IUBMB Life, 2009
Human erythropoiesis is a complex multistep developmental process that begins at the level of pluripotent hematopoietic stem cells (HSCs) at bone marrow microenvironment (HSCs niche) and terminates with the production of erythrocytes (RBCs). This review covers the basic and contemporary aspects of erythropoiesis. These include the: (a) cell-lineage restricted pathways of differentiation originated from HSCs and going downward toward the blood cell development; (b) model systems employed to study erythropoiesis in culture (erythroleukemia cell lines and embryonic stem cells) and in vivo (knockout animals: avian, mice, zebrafish, and xenopus); (c) key regulators of erythropoiesis (iron, hypoxia, stress, and growth factors); (d) signaling pathways operating at hematopoietic stem cell niche for homeostatic regulation of self renewal (SCF/c-kit receptor, Wnt, Notch, and Hox) and for erythroid differentiation (HIF and EpoR). Furthermore, this review presents the mechanisms through which transcriptional factors (GATA-1, FOG-1, TAL-1/ SCL/MO2/Ldb1/E2A, EKLF, Gfi-1b, and BCL11A) and miR-NAs regulate gene pattern expression during erythroid differentiation. New insights regarding the transcriptional regulation of aand b-globin gene clusters were also presented. Emphasis was also given on (i) the developmental program of erythropoiesis, which consists of commitment to terminal erythroid maturation and hemoglobin production, (two closely coordinated events of erythropoieis) and (ii) the capacity of human embryonic and umbilical cord blood (UCB) stem cells to differentiate and produce RBCs in culture with highly selective media. These most recent developments will eventually permit customized red blood cell production needed for transfusion. 2009 IUBMB IUBMB Life, 61(8): 800-830, 2009
Proceedings of the National Academy of Sciences, 1988
To test directly whether the control of fetal hemoglobin (HbF) in the adult takes place at the level of erythroid progenitors or at the level of erythroblasts, we treated animals with high doses oferythropoietin and examined the effects of this manipulation on the globin gene programs of erythroid progenitors. We found that administration of erythropoietin produced a rapid expansion of all classes of erythroid progenitors. Almost all the expansion of colonyforming units-erythroid and 46-56% of erythroid clusters was due to the increase of HbF-programmed erythroid progenitors. The expansion of HbF-programmed erythroid progenitors was followed, 2-3 days later, by a wave of reticulocytes containing HbF in the peripheral blood. These results provide direct in vivo evidence that fetal-globin expression in the adult is controlled at the level of erythroid progenitors.
Primitive erythropoiesis in the mammalian embryo
The International Journal of Developmental Biology, 2010
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.
Scientific Reports
The β-thalassemia syndromes are the most prevalent genetic disorder globally, characterised by reduced or absent β-globin chain synthesis. HbE/β-thalassemia is a subtype of β-thalassemia with extremely high frequency in Asia. Studying molecular defects behind β-thalassemia is severely impeded by paucity of material from patients and lack of suitable cell lines. Approaches to derive erythroid cells from induced pluripotent stem cells (iPSCs) created from patients are confounded by poor levels of erythroid cell expansion, aberrant or incomplete erythroid differentiation and foetal/embryonic rather than adult globin expression. In this study we generate an immortalised erythroid cell line from peripheral blood stem cells of a HbE/β-thalassemia patient. Morphological analysis shows the cells are proerythroblasts with some early basophilic erythroblasts, with no change in morphology over time in culture. The line differentiates along the erythroid pathway to orthochromatic erythroblasts ...
Determination of the hemoglobin F program in human progenitor-derived erythroid cells
Journal of Clinical Investigation, 1985
The absolute adult and fetal hemoglobin (HbF) contents of the erythroid cells derived from the differentiation of normal human and simian erythroid progenitors and of the peripheral blood erythroid burst-forming units (BFU-E) of patients with nondeletion hemoglobinopathies have been measured with a sensitive radioligand immunoassay. The HbF content varied between 0.13 and 2.96 pg/cell, representing between 0.7% and 19.