Erythroid cell differentiation

L.H. Conder, S. I. Woodard, H. A. Dailey (1991). Multiple mechanisms for the regulation of heme synthesis during erythroid cell differentiation. Possible role for coproporphyrinogen oxidase. Biochem. J., 275, 321-326. 

Erythroid Cell Differentiation and the Synthesis and Assembly of Hemoglobin... 

ERYTHROID CELL DIFFERENTIATION AND THE INDUCTION OF HEMOGLOBIN SYNTHESIS... 

Hematopoiesis is defined as the development and maturation of blood cells and their precursors. In utero, hematopoiesis may occur in the liver, spleen, and bone marrow. However, after birth, it occurs exclusively in the bone marrow. All blood cells are generated from a common hematopoietic precursor, or stem cell. These stem cells are self-renewing and pluripotent and thus are able to commit to any one of the different lines of maturation that give rise to platelet-producing megakaryocytes, lymphoid, erythroid, and myeloid cells. The myeloid cell line produces monocytes, basophils, neutrophils, and eosinophils, whereas the lymphoid stem cell differentiates to form circulating B and T lymphocytes. In contrast to the ordered development of normal cells, the development of leukemia seems to represent an arrest in differentiation at an early phase in the continuum of stem cell to mature cell.1... 

Erythropoietin is a glycoprotein hormone that regulates the proliferation, differentiation, and maturation of erythroid cells. The EPO receptor is a member of the class 1 cytokine receptor superfamily. The crystal structure of an EPO-mimetic peptide and the extracellular portion of the... 

Figure 17.10 Flow cytometric method does not differentiate between nucleated erythroid cells and reticulocytes, on some instruments. Non-nucleated e throid cells were isolated using cellulose fractionation. Part of the sample was stained with Wright-Giemsa and reticulocytes and mature nucleated cells quantified by trained medical technologists.

The regulation of hematopoiesis in the bone marrow is not only controlled by the cytokine composition, the cells microenvironment and the oxygen tension, but, as shown recently [55], also by the local pH. For cells of different Hneages deviating pH optima have been described. While CFU-GM proliferate best in a pH range 7.2 - 7.4 (the normal pH of blood), for erythroid cells an optimum of pH 7.6 was found. Below an acidic pH of 6.7 no differentiation or proUferation of any hematopoietic cell was observed. Cells of the erythroid lineage are even strongly inhibited at a pH below 7.1 [56]. 

The process of erythropoiesis has been reviewed by Harrison (1976, 1977) and Orkin (1978) and more recently Metcalf (1989) has reviewed haemopoiesis from the molecular point of view. Erythroid cells together with the other blood cells are derived from a common haematopoietic stem cell. After commitment to the erythroid lineage the stem cells proliferate for a few generations when they become sensitive to the hormone erythropoietin which increases the proliferation of committed erythroid stem cells and proerythroblasts which then differentiate into mature erythroid cells containing haemoglobin. 

The parenchymatous liver cells (hepatocytes) hold a key position in the overall metabolism of iron (57, 58, 59, 60), and since functionally intact liver mitochondria can be conveniently prepared at high yield, these mitochondria have been most extensively studied so far. The iron transporting system discussed above for liver mitochondria is present also in mitochondria from other tissues and animal species (Table III). Quantitatively, erythroid cells of the bone marrow play the most important role in the overall metabolism of iron (61), and it was therefore not unexpected to find that the energized uptake of iron by isolated reticulocyte mitochondria exceeds that of mitochondria isolated from, for example, liver, kidney, and heart (Table IV). Thus, a relationship appears to exist between the rate and extent of heme protein turnover in mitochondria isolated from different tissues and their energized iron accumulation (30). Thus, it is evident that cellular differentiation is expressed at the mitochondrial level by modulation of the activity of essential functions related to iron transport and heme biosynthesis. 

Benzene, administered intraperitoneally at 600 mg/kg in com oil, 2 times per day for 2 days to male C57BL/6J mice, caused a significant depression in the total number of nucleated bone marrow cells per femur, when measured on day 3 (Niculescu and Kalf 1995). Additional experiments with 7-day exposure revealed that there was an initial depression in erythroid cells on day 3 which remained constant lymphocytes exhibited a progressively depressive effect, and the numbers of intermediate and terminally differentiated granulocytes exhibited a progressive increase over the 7 days of exposure. Upon cessation of the benzene treatment, the bone marrow appeared to begin recovery, with the number of nucleated cells equal to control animals by day 7 after treatment ended. Concomitant administration of IL-la prevented the decrease in nucleated bone marrow cells, whereas IL-la administered after 2 days of benzene exposure significantly increased the rate of recovery of bone marrow cellularity. 

An additional emerging possibility of regulation of heme biosynthesis in differentiating erythroid cells resides at the ALAS2 mRNA translational level. ALAS2 synthesis is intimately related to the availability of iron. An iron-responsive ele-... 

C. Tringali, L. Anastasia, N. Papini, A. Bianchi, L. Ronzoni, M. D. Cappellini, E. Monti, G. Tettamanti, and B. Venerando, Modification of sialidase levels and sialoglycoconjugate pattern during erythroid and eiythroleukemic cell differentiation, Glycoconj. J., 24 (2007) 67-79. 

Bungert, J., Waldschmidt, R., Kober, I. Seifart, K.H. (1992). TransCTiption factor-IIA is inactivated during terminal differentiation of avian erythroid-cells. Proc. Natl. Acad. Sci. USA, 89, 11678-82. 

Analysis by RT-PCR of expression of a panel of hematopoietic markers indicated that visceral endoderm signaling results in activation not only of genes characteristic of differentiated erythroid cells globin) but also of early hematopoietic genes such as GATA-1 and CD-34. The presence of VE in recombinants did not result in promiscuous activation of mesoderm differentiation markers cardiac myosin, which is expected to be expressed only in cardiac tissue (and therefore only at a later developmental stage), was not detected in anterior or posterior epiblast pieces or in recombinants during the first 4 days in culture, but was detected in an older (10.5 dpc) embryonic control. 

All aerobic cells contain heme and closely related iron porphyrins these serve as the prosthetic groups of hemoproteins such as cytochromes and catalase. The amount of heme made by a stem cell or proerythroblast is minute compared with that which is required for hemoglobinization to form an erythroid cell. In the differentiation of the proerythroblast to erythroid cell the synthesis of heme as well as of globin must be turned on fully. 

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