Maturation-associated gene expression profiles during normal human bone marrow erythropoiesis

Abstract

Erythropoiesis has been extensively studied using in vitro and in vivo animal models. Despite this, there is still limited data about the gene expression profiles (GEP) of primary (ex vivo) normal human bone marrow (BM) erythroid maturation. We investigated the GEP of nucleated red blood cell (NRBC) precursors during normal human BM erythropoiesis. Three maturation-associated populations of NRBC were identified and purified from (fresh) normal human BM by flow cytometry and the GEP of each purified cell population directly analyzed using DNA-oligonucleotide microarrays. Overall, 6569 genes (19% of the genes investigated) were expressed in ≥1 stage of BM erythropoiesis at stable (e.g., genes involved in DNA process, cell signaling, protein organization and hemoglobin production) or variable amounts (e.g., genes related to cell differentiation, apoptosis, metabolism), the latter showing a tendency to either decrease from stage 1 to 3 (genes associated with regulation of erythroid differentiation and survival, e.g., SPI1 , STAT5A ) or increase from stage 2 to stage 3 (genes associated with autophagy, erythroid functions such as heme production, e.g., ALAS1 , ALAS2), iron metabolism (e.g., ISCA1, SLC11A2 ), protection from oxidative stress (e.g., UCP2 , PARK7 ), and NRBC enucleation (e.g., ID2 , RB1 ). Interestingly, genes involved in apoptosis (e.g., CASP8, P2RX1 ) and immune response (e.g., FOXO3, TRAF6 ) were also upregulated in the last stage (stage 3) of maturation of NRBC precursors. Our results confirm and extend on previous observations and providing a frame of reference for better understanding the critical steps of human erythroid maturation and its potential alteration in patients with different clonal and non-clonal erythropoietic disorders.

A new role of glutathione peroxidase 4 during human erythroblast enucleation

“…GPX4 was highly expressed in our culture system of human erythroid differentiation, reaching a peak at day 6 that corresponds to erythroblast exponential amplification associated with higher transferrin receptor expression and the beginning of hemoglobin synthesis. [49][50][51] Because erythroblasts require a high bioavailable iron concentration to synthesize hemoglobin, a seducing hypothesis would be that GPX4 would protect these cells with an elevated cellular iron pool from ferroptosis. However, no significant impact of GPX4 inhibition in terms of cell death was observed during erythroblast differentiation.…”

A Review of the Action of Magnesium on Several Processes Involved in the Modulation of Hematopoiesis

“…Erythropoiesis occurs from pluripotent stem cells in the bone marrow, with the erythroid progenitor being BFU-E (erythroid explosion-forming unit), which results in colony-forming units (CFU-E), mature erythroid precursors, reticulocytes, and red blood cells [ 126 ]. Erythroid differentiation and maturation occur in erythroblastic islands, and these complex events of proliferation, differentiation, and maturation depend on several factors, such as GATA-binding protein 1 and 2 (GATA 1 and 2), SCF, IGF (insulin-like growth factor), BPA (erythroid burst-promoting activity), IL-3, and EPO (erythropoietin) [ 127 , 128 , 129 , 130 ], in addition to nutritional aspects, like iron, folate, and B12 vitamin [ 131 ]. Yet, the influence of Mg 2+ on the erythropoiesis process in the bone marrow is not clear.…”

Heme metabolism genes Downregulated in COPD Cachexia

“…A genome-wide expression study of skeletal muscle biopsies from upper gastro-intestinal cancer patients highlighted ALAS1 as downregulated in patients with cancer cachexia [27]. ALAS2 and ALAS1 encode the same enzyme, 5′-Aminolevuilnnate Synthetase, which plays a key role in heme synthesis [28]. Previous studies have demonstrated that ALAS1 and ALAS2 expression levels are increased during erythropoiesis in healthy individuals [28].…”

“…ALAS2 and ALAS1 encode the same enzyme, 5′-Aminolevuilnnate Synthetase, which plays a key role in heme synthesis [28]. Previous studies have demonstrated that ALAS1 and ALAS2 expression levels are increased during erythropoiesis in healthy individuals [28]. ALAS2 is erythroid-specific whereas ALAS1 is expressed in many tissues, including skeletal muscle.…”

“…PLEK2 encodes pleckstrin-2, a protein playing a critical role in the protection of erythroblasts from oxidative damage [37]. Specifically, PLEK2 functions in the structural organization of the erythroblast to prevent the localization of cofilin (an actin-binding protein) to the mitochondria where it induces apoptosis [28,37]. Previous studies have demonstrated pleckstrin-2 knockout results in erythrocyte apoptosis and inhibition of differentiation, a precursor to cell-free iron loading [37].…”