Biochemical measurements on single erythroid progenitor cells shed light on the combinatorial regulation of red blood cell production

2013 ◽  
Vol 9 (2) ◽  
pp. 234-245 ◽  
Author(s):  
Weijia Wang ◽  
Vahe Akbarian ◽  
Julie Audet
Keyword(s):  
Blood Cell ◽  
Progenitor Cells ◽  
Red Blood Cell ◽  
Erythroid Progenitor ◽  
Combinatorial Regulation ◽  
Cell Production ◽  
Erythroid Progenitor Cells ◽  
Biochemical Measurements ◽  
Shed Light

Regulation and function of transcription factor GATA-1 during red blood cell differentiation

Development ◽  
1996 ◽  
Vol 122 (12) ◽  
pp. 3839-3850 ◽  
Author(s):  
K. Briegel ◽  
P. Bartunek ◽  
G. Stengl ◽  
K.C. Lim ◽  
H. Beug ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Transcription Factor ◽  
Cell Differentiation ◽  
Blood Cell ◽  
Progenitor Cells ◽  
Red Blood Cell ◽  
Nuclear Translocation ◽  
Erythroid Progenitor ◽  
Erythroid Progenitor Cells ◽  
Induction Of Differentiation

The tissue-specific transcription factor GATA-1 is a key regulator of red blood cell differentiation. One seemingly contradictory aspect of GATA-1 function is that, while it is abundant in erythroid progenitor cells prior to the onset of overt differentiation, it does not significantly activate known GATA-1 target genes in those cells. To investigate the mechanisms underlying GATA-1 function during the transition from early to late erythropoiesis, we have examined its expression and activity in normal avian erythroid progenitor cells before and after induction of differentiation. In these primary progenitor cells, GATA-1 protein was predominantly located in the cytoplasm, while induction of differentiation caused its rapid relocalization to the nucleus, suggesting that nuclear translocation constitutes an important regulatory step in GATA-1 activation. As an alternative way of addressing the same question, we also ectopically expressed a GATA-1/estrogen receptor fusion protein (GATA-1/ER) in red blood cell progenitors, where nuclear translocation of, and transcriptional activation by, this hybrid factor are conditionally controlled by estrogen. We found that hormone-activated GATA-1/ER protein accelerated red blood cell differentiation, and concomitantly suppressed cell proliferation. These phenotypic effects were accompanied by a simultaneous suppression of c-myb and GATA-2 transcription, two genes thought to be involved in the proliferative capacity of hematopoietic progenitor cells. Thus, GATA-1 appears to promote differentiation in committed erythroid progenitor cells both by inducing differentiation-specific genes and by simultaneously suppressing genes involved in cell proliferation.

Role for BH3-Only Protein NOXA In Growth-Factor Deprivation and Early Erythropoiesis

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4235-4235
Author(s):  
Christian R. Geest ◽  
Felix M. Wensveen ◽  
Sten F.W.M. Libregts ◽  
Alex M. de Bruin ◽  
Ingrid A.M. Derks ◽  
...  
Keyword(s):  
Growth Factor ◽  
Blood Cell ◽  
Red Blood Cell ◽  
Erythroid Cell ◽  
Erythroid Progenitors ◽  
Erythroid Progenitor ◽  
Apoptosis Pathway ◽  
Cell Production ◽  
Growth Factor Deprivation ◽  
Redundant Role

Abstract Abstract 4235 Red blood cell production is a strictly regulated process and homeostatic maintenance of the erythropoietic system requires equilibrium between the rate of erythroid cell production and red blood cell destruction. Hematopoietic cytokines play a crucial role in regulating expansion, differentiation and survival of erythrocyte progenitors. Shortage of growth factors triggers the mitochondrial apoptosis pathway, which is critically dependent on Bcl-2 family members. However, the contribution of this mechanism in the regulation of erythropoiesis remains ill-defined. This prompted us to screen for candidate genes involved in this process in erythroid progenitors. We found that the expression of Noxa, a pro-apoptotic Bcl-2 family member, is upregulated during erythroid differentiation and following cytokine-withdrawal in erythroid progenitor cells. Knockdown or deletion of Noxa in IL-3 dependent human and murine erythroid progenitor cell lines increased Mcl-1 levels, which correlated with markedly decreased apoptosis following cytokine withdrawal. Importantly, Noxa ablation in mice increased extra-medullary erythropoiesis, resulting in enhanced numbers of early splenic erythroblasts and circulating reticulocytes. Noxa-deficient hematopoietic progenitors were more resistant to apoptosis induced by growth factor deprivation and displayed increased colony-forming potential. In addition, combined loss of Noxa and Bim resulted in enhanced resistance of erythroid progenitors to cytokine withdrawal compared to WT or single Bim knockouts, suggesting a non-redundant role for Noxa and Bim in regulating survival of erythroid progenitors in response to cytokine deprivation. Finally, in a model of acute haemolytic anaemia, deletion of Noxa enhanced subsequent hematocrit recovery. Together, these findings identify a non-redundant role for BH3-only protein Noxa in the regulation of erythroblast survival during early erythropoiesis. Therefore, Noxa may be a novel component to control red blood cell numbers and modulation of this pathway could be envisaged in therapeutic options for treatment of anaemia. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Erythropoietin in Brain Development and Beyond

2012 ◽  
Vol 2012 ◽  
pp. 1-15 ◽  
Author(s):  
Mawadda Alnaeeli ◽  
Li Wang ◽  
Barbora Piknova ◽  
Heather Rogers ◽  
Xiaoxia Li ◽  
...  
Keyword(s):  
Blood Cell ◽  
Red Blood Cell ◽  
Cell Types ◽  
Erythropoietin Receptor ◽  
Adult Brain ◽  
Receptor Expression ◽  
Neural Cells ◽  
Erythroid Progenitor ◽  
Cell Production ◽  
Oxygen Carrying Capacity

Erythropoietin is known as the requisite cytokine for red blood cell production. Its receptor, expressed at a high level on erythroid progenitor/precursor cells, is also found on endothelial, neural, and other cell types. Erythropoietin and erythropoietin receptor expression in the developing and adult brain suggest their possible involvement in neurodevelopment and neuroprotection. During ischemic stress, erythropoietin, which is hypoxia inducible, can contribute to brain homeostasis by increasing red blood cell production to increase the blood oxygen carrying capacity, stimulate nitric oxide production to modulate blood flow and contribute to the neurovascular response, or act directly on neural cells to provide neuroprotection as demonstrated in culture and animal models. Clinical studies of erythropoietin treatment in stroke and other diseases provide insight on safety and potential adverse effects and underscore the potential pleiotropic activity of erythropoietin. Herein, we summarize the roles of EPO and its receptor in the developing and adult brain during health and disease, providing first a brief overview of the well-established EPO biology and signaling, its hypoxic regulation, and role in erythropoiesis.

Epo-Independent Proliferation and Differentiation of Genetically Modified Erythroid Progenitor Cells Using a Chemical Inducer of Dimerization.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1159-1159
Author(s):  
Chris P. Miller ◽  
Songmao Zheng ◽  
C. Anthony Blau
Keyword(s):  
Progenitor Cells ◽  
Erythroid Cell ◽  
Glycophorin A ◽  
Erythroid Cells ◽  
Erythroid Progenitor ◽  
Cell Production ◽  
Erythroid Progenitor Cells ◽  
Proliferation And Differentiation ◽  
Cells Cultured ◽  
Chemical Inducer Of Dimerization

Abstract Recombinant human erythropoietin (Epo) revolutionized the care of anemia in cancer. In light of emerging (albeit controversial) roles for Epo in supporting tumor growth, it may be useful to develop Epo-independent methods for regulating red blood cell production. Previous studies in this laboratory established that marrow transduced with conditional derivatives of fibroblast growth factor receptor-1 (F36VFGFR1) and the thrombopoietin receptor (F36VMpl) can support the chemical inducer of dimerization (CID)-dependent production of erythroid cells in transplanted mice. In the current study, we used human CD34+ cord blood (CB) cells to test whether CID-regulated red cell production might require collaboration between CID-initiated signals and those provided by Epo. CD34+ CB cells cultured in the absence of Epo did not proliferate and retained expression of the myeloid marker CD33. Epo (5U/mL) promoted proliferative expansion (66.2-fold in 12 days) and CD33 expression was lost as the cells differentiated to mature, glycophorin A+ erythroid cells (92.9 +/− 1.8%, n=3). Addition of a soluble human Epo receptor extracellular domain (shEpoR) at a concentration of 3ug/mL completely blocked Epo-dependent proliferation and similar to cells cultured without Epo, they retained expression of CD33. Addition of CID (100nM AP20187) to F36VMpl-transduced CD34+ CB cells in the absence of Epo promoted proliferative expansion (89.8-fold in 12 days) and differentiation as glycophorin A+ erythroid cells (77.2 +/− 4.8%, n=3). These CID responses were not significantly affected by the addition of shEpoR, as CID induced both mitogenic expansion (84.5 fold in 12 days) and differentiation as glycophorin A+ erythroid cells (74.2 +/− 6.7%, n=3) in the presence of concentrations of shEpoR that blocked Epo responses. These data suggest that F36VMpl does not require Epo signaling to support the proliferation and differentiation of human erythroid progenitor cells, and further define an Epo-independent method of erythroid cell production.

Human thymic epithelial cells maintain long-term survival of clonogenic myeloid and erythroid progenitor cells in vitro

2000 ◽  
Vol 111 (1) ◽  
pp. 363-370 ◽  
Author(s):  
Katsuto Takenaka ◽  
Mine Harada ◽  
Tomoaki Fujisaki ◽  
Koji Nagafuji ◽  
Shinichi Mizuno ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Progenitor Cells ◽  
Thymic Epithelial Cells ◽  
Erythroid Progenitor ◽  
Term Survival ◽  
Long Term Survival ◽  
Erythroid Progenitor Cells

scholarly journals Fetal erythropoiesis in steel mutant mice. III. Defect in differentiation from BFU-E to CFU-E during early development

Blood ◽  
1978 ◽  
Vol 51 (3) ◽  
pp. 539-547 ◽  
Author(s):  
DH Chui ◽  
SK Liao ◽  
K Walker
Keyword(s):  
Progenitor Cells ◽  
Early Development ◽  
The Other ◽  
Mutant Mice ◽  
Erythroid Progenitor ◽  
Erythroid Progenitor Cells ◽  
Other Hand ◽  
Colony Forming Units ◽  
Fetal Erythropoiesis

Abstract Erythroid progenitor cells in +/+ and Sl/Sld fetal livers manifested as burst-forming units-erythroid (BFU-E) and colony-forming units- erythroid (CFU-E) were assayed in vitro during early development. The proportion of BFU-E was higher as mutant than in normal fetal livers. On the other hand, the proportion of CFU-E was less in the mutant than in the normal. These results suggest that the defect in Sl/Sld fetal hepatic erythropoiesis is expressed at the steps of differentiation that effect the transition from BFU-E to CFU-E.

scholarly journals The Raf‐1 Protein Mediates Insulin‐Like Growth Factor‐Induced Proliferation of Erythroid Progenitor Cells

Stem Cells ◽  
1998 ◽  
Vol 16 (3) ◽  
pp. 200-207 ◽  
Author(s):  
Marilyn R. Sanders ◽  
Hsienwie Lu ◽  
Frederick Walker ◽  
Sandra Sorba ◽  
Nicholas Dainiak
Keyword(s):  
Growth Factor ◽  
Progenitor Cells ◽  
Erythroid Progenitor ◽  
Erythroid Progenitor Cells

scholarly journals Tumor Immune Evasion Induced by Dysregulation of Erythroid Progenitor Cells Development

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 870
Author(s):  
Tomasz M. Grzywa ◽  
Magdalena Justyniarska ◽  
Dominika Nowis ◽  
Jakub Golab
Keyword(s):  
T Cells ◽  
Tumor Growth ◽  
Progenitor Cells ◽  
Cancer Progression ◽  
Immune Evasion ◽  
Transforming Growth Factor ◽  
Early Stage ◽  
Interleukin 10 ◽  
Erythroid Progenitor ◽  
Erythroid Progenitor Cells

Cancer cells harness normal cells to facilitate tumor growth and metastasis. Within this complex network of interactions, the establishment and maintenance of immune evasion mechanisms are crucial for cancer progression. The escape from the immune surveillance results from multiple independent mechanisms. Recent studies revealed that besides well-described myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs) or regulatory T-cells (Tregs), erythroid progenitor cells (EPCs) play an important role in the regulation of immune response and tumor progression. EPCs are immature erythroid cells that differentiate into oxygen-transporting red blood cells. They expand in the extramedullary sites, including the spleen, as well as infiltrate tumors. EPCs in cancer produce reactive oxygen species (ROS), transforming growth factor β (TGF-β), interleukin-10 (IL-10) and express programmed death-ligand 1 (PD-L1) and potently suppress T-cells. Thus, EPCs regulate antitumor, antiviral, and antimicrobial immunity, leading to immune suppression. Moreover, EPCs promote tumor growth by the secretion of growth factors, including artemin. The expansion of EPCs in cancer is an effect of the dysregulation of erythropoiesis, leading to the differentiation arrest and enrichment of early-stage EPCs. Therefore, anemia treatment, targeting ineffective erythropoiesis, and the promotion of EPC differentiation are promising strategies to reduce cancer-induced immunosuppression and the tumor-promoting effects of EPCs.

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