mDYRK3 kinase is expressed selectively in late erythroid progenitor cells and attenuates colony-forming unit–erythroid development

Blood ◽  
2001 ◽  
Vol 97 (4) ◽  
pp. 901-910 ◽  
Author(s):  
Justin N. Geiger ◽  
Geoffry T. Knudsen ◽  
Leigh Panek ◽  
Ajay K. Pandit ◽  
Michael D. Yoder ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Cell Cycle Progression ◽  
Fetal Liver ◽  
Hematopoietic Cells ◽  
Erythroid Cell ◽  
Erythroid Progenitor ◽  
Colony Forming Unit ◽  
Erythroid Progenitor Cells ◽  
Dual Specificity

Abstract DYRKs are a new subfamily of dual-specificity kinases that was originally discovered on the basis of homology to Yak1, an inhibitor of cell cycle progression in yeast. At present, mDYRK-3 and mDYRK-2 have been cloned, and mDYRK-3 has been characterized with respect to kinase activity, expression among tissues and hematopoietic cells, and possible function during erythropoiesis. In sequence, mDYRK-3 diverges markedly in noncatalytic domains from mDYRK-2 and mDYRK-1a, but is 91.3% identical overall to hDYRK-3. Catalytically, mDYRK-3 readily phosphorylated myelin basic protein (but not histone 2B) and also appeared to autophosphorylate in vitro. Expression of mDYRK-1a, mDYRK-2, and mDYRK-3 was high in testes, but unlike mDYRK1a and mDYRK 2, mDYRK-3 was not expressed at appreciable levels in other tissues examined. Among hematopoietic cells, however, mDYRK-3 expression was selectively elevated in erythroid cell lines and primary pro-erythroid cells. In developmentally synchronized erythroid progenitor cells, expression peaked sharply following exposure to erythropoietin plus stem cell factor (SCF) (but not SCF alone), and in situ hybridizations of sectioned embryos revealed selective expression of mDYRK-3 in fetal liver. Interestingly, antisense oligonucleotides to mDYRK-3 were shown to significantly and specifically enhance colony-forming unit–erythroid colony formation. Thus, it is proposed that mDYRK-3 kinase functions as a lineage-restricted, stage-specific suppressor of red cell development.

scholarly journals Pregnancy-Secreted Acid Phosphatase, Uteroferrin, Enhances Fetal Erythropoiesis

Endocrinology ◽  
2014 ◽  
Vol 155 (11) ◽  
pp. 4521-4530 ◽  
Author(s):  
Wei Ying ◽  
Haiqing Wang ◽  
Fuller W. Bazer ◽  
Beiyan Zhou
Keyword(s):  
Acid Phosphatase ◽  
Progenitor Cells ◽  
Fetal Liver ◽  
Hematopoietic Cells ◽  
Erythroid Progenitor ◽  
Colony Forming Unit ◽  
Erythroid Progenitor Cells ◽  
Uterine Glands ◽  
Fetal Erythropoiesis

Abstract Uteroferrin (UF) is a progesterone-induced acid phosphatase produced by uterine glandular epithelia in mammals during pregnancy and targeted to sites of hematopoiesis throughout pregnancy. The expression pattern of UF is coordinated with early fetal hematopoietic development in the yolk sac and then liver, spleen, and bone to prevent anemia in fetuses. Our previous studies suggested that UF exerts stimulatory impacts on hematopoietic progenitor cells. However, the precise role and thereby the mechanism of action of UF on hematopoiesis have not been investigated previously. Here, we report that UF is a potent regulator that can greatly enhance fetal erythropoiesis. Using primary fetal liver hematopoietic cells, we observed a synergistic stimulatory effect of UF with erythropoietin and other growth factors on both burst-forming unit-erythroid and colony-forming unit-erythroid formation. Further, we demonstrated that UF enhanced erythropoiesis at terminal stages using an in vitro culture system. Surveying genes that are crucial for erythrocyte formation at various stages revealed that UF, along with erythropoietin, up-regulated transcription factors required for terminal erythrocyte differentiation and genes required for synthesis of hemoglobin. Collectively, our results demonstrate that UF is a cytokine secreted by uterine glands in response to progesterone that promotes fetal erythropoiesis at various stages of pregnancy, including burst-forming unit-erythroid and colony-forming unit-erythroid progenitor cells and terminal stages of differentiation of hematopoietic cells in the erythroid lineage.

scholarly journals Ligand-dependent repression of the erythroid transcription factor GATA-1 by the estrogen receptor.

1995 ◽  
Vol 15 (6) ◽  
pp. 3147-3153 ◽  
Author(s):  
G A Blobel ◽  
C A Sieff ◽  
S H Orkin
Keyword(s):  
Bone Marrow ◽  
Estrogen Receptor ◽  
Transcription Factor ◽  
Progenitor Cells ◽  
Erythroid Cell ◽  
High Dose ◽  
Dependent Manner ◽  
Erythroid Progenitor ◽  
Erythroid Progenitor Cells

High-dose estrogen administration induces anemia in mammals. In chickens, estrogens stimulate outgrowth of bone marrow-derived erythroid progenitor cells and delay their maturation. This delay is associated with down-regulation of many erythroid cell-specific genes, including alpha- and beta-globin, band 3, band 4.1, and the erythroid cell-specific histone H5. We show here that estrogens also reduce the number of erythroid progenitor cells in primary human bone marrow cultures. To address potential mechanisms by which estrogens suppress erythropoiesis, we have examined their effects on GATA-1, an erythroid transcription factor that participates in the regulation of the majority of erythroid cell-specific genes and is necessary for full maturation of erythrocytes. We demonstrate that the transcriptional activity of GATA-1 is strongly repressed by the estrogen receptor (ER) in a ligand-dependent manner and that this repression is reversible in the presence of 4-hydroxytamoxifen. ER-mediated repression of GATA-1 activity occurs on an artificial promoter containing a single GATA-binding site, as well as in the context of an intact promoter which is normally regulated by GATA-1. GATA-1 and ER bind to each other in vitro in the absence of DNA. In coimmunoprecipitation experiments using transfected COS cells, GATA-1 and ER associate in a ligand-dependent manner. Mapping experiments indicate that GATA-1 and the ER form at least two contacts, which involve the finger region and the N-terminal activation domain of GATA-1. We speculate that estrogens exert effects on erythropoiesis by modulating GATA-1 activity through protein-protein interaction with the ER. Interference with GATA-binding proteins may be one mechanism by which steroid hormones modulate cellular differentiation.

UCP2 Modulates Cell Proliferation through the MAPK/ERK Pathway during Erythropoiesis and Has No Effect on Heme Biosynthesis

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5372-5372
Author(s):  
Alvaro A Elorza ◽  
Brigham B Hyde ◽  
Hanna Mikkola ◽  
Sheila Collins ◽  
Orian S Shirihai
Keyword(s):  
Cell Proliferation ◽  
Progenitor Cells ◽  
Fetal Liver ◽  
Mitochondrial Protein ◽  
Erythroid Progenitor ◽  
Heme Synthesis ◽  
Erythroid Progenitor Cells ◽  
Deficient Mice

Abstract UCP2, an inner membrane mitochondrial protein, has been implicated in bioenergetics and Reactive Oxygen Species (ROS) modulation. UCP2 has been previously hypothesized to function as a facilitator of heme synthesis and iron metabolism by reducing ROS production. While UCP2 has been found to be induced by GATA1 during erythroid differentiation its role in erythropoiesis in vivo or in vitro has not been reported thus far. Here we report on the study of UCP2 role in erythropoiesis and the hematologic phenotype of UCP2 deficient mouse. In vivo we found that UCP2 protein peaks at early stages of erythroid maturation when cells are not fully committed in heme synthesis and then becomes undetectable at the reticulocyte stage. Iron incorporation into heme was unaltered in erythroid cells from UCP2 deficient mice. While heme synthesis was not influenced by UCP2 deficiency, mice lacking UCP2 had a delayed recovery from chemically induced hemolytic anemia. Analysis of the erythroid lineage from bone marrow and fetal liver revealed that in the UCP2 deficient mice the R3 (CD71high/Ter119high) population was reduced by 24%. The count of BFU-E and CFU-E colonies, scored in an erythroid colony assay, was unaffected, indicating an equivalent number of early erythroid progenitor cells in both UCP2 deficient and control cells. Ex-vivo differentiation assay revealed that UCP2 deficient c-kit+ progenitor cells expansion was overall reduced by 14% with population analysis determining that the main effect is at the R3 stage. No increased rate of apoptosis was found indicating that expansion rather than cell death is being compromised. Reduced expansion of c-kit+ cells was accompanied by 30% reduction in the phosphorylated form of ERK, a ROS dependent cytosolic regulator of cell proliferation. Analysis of ROS in UCP2 null erythroid progenitors revealed altered distribution of ROS resulting in 14% decrease in cytosolic and 32% increase in mitochondrial ROS. Restoration of the cytosolic oxidative state of erythroid progenitor cells by the pro-oxidant Paraquat reversed the effect of UCP2 deficiency on cell proliferation in in vitro differentiation assays. Together, these results indicate that UCP2 is a regulator of erythropoiesis and suggests that inhibition of UCP2 function may contribute to the development of anemia.

scholarly journals Abnormal erythroid progenitor cells in human preleukemia

Blood ◽  
1982 ◽  
Vol 60 (2) ◽  
pp. 362-367 ◽  
Author(s):  
DH Chui ◽  
BJ Clarke
Keyword(s):  
Progenitor Cells ◽  
Peripheral Blood ◽  
Culture Technique ◽  
The Other ◽  
Erythroid Cell ◽  
Erythroid Progenitor ◽  
Clonal Culture ◽  
Erythroid Progenitor Cells ◽  
Marrow Cells

Abstract Ten patients with preleukemia were studied by the erythroid cell clonal culture technique. In nine of these patients, erythroid colonies derived from peripheral blood BFU-E were not observed, while the other patient had markedly decreased peripheral blood BFU-E-derived erythroid colonies in vitro. In three patients, marrow cells were also cultured and no BFU-E-derived erythroid colonies were detected. These studies indicate that immature erythroid progenitor cells, BFU-E, in patients with preleukemia are either markedly decreased in number or grossly defective in their proliferative or differentiative capacities.

scholarly journals Isolation of murine fetal hemopoietic progenitor cells and selective fractionation of various erythroid precursors

Blood ◽  
1981 ◽  
Vol 58 (2) ◽  
pp. 376-386 ◽  
Author(s):  
NA Nicola ◽  
D Metcalf ◽  
H von Melchner ◽  
AW Burgess
Keyword(s):  
Progenitor Cells ◽  
Fetal Liver ◽  
Pokeweed Mitogen ◽  
Erythroid Progenitor ◽  
Clonal Proliferation ◽  
Erythroid Progenitor Cells ◽  
Blast Cells ◽  
Hemopoietic Progenitor ◽  
Hemopoietic Progenitor Cells

Abstract Hemopoietic progenitor cells (colony- and cluster-forming cells in semisolid agar) were purified from light density CBA murine fetal liver cells using fluorescein-conjugated pokeweed mitogen (PWM) and a rhodamine-conjugated antineutrophil serum sandwich (alpha N) and three- parameter fluorescence-activated cell sorting. All clonable progenitor cells were highly enriched (36–50-fold) in PWM-positive (greater than channel 15), alpha N-negative (less than channel 30) fractions with relatively high intensity (greater than 100) low angle light scatter. No separation was achieved between different types of progenitor cells (granulocyte-macrophage and erythroid colony-forming cells). The enriched fraction was a pure population of large, basophilic, undifferentiated blast cells, and in agar cultures stimulated with colony-stimulating factors, up to 90% of the enriched cells were hemopoietic progenitor cells capable of varying levels of clonal proliferation. Further fractionation based on increasing fluorescence with PWM separated into discrete populations, nonproliferative morphologically recognizable erythroid cells, late erythroid progenitor cells (day 2 CFU-E), and cells forming pure or mixed erythroid burst colonies. In addition, the majority of pluripotential hemopoietic stem cells (CFU-SS) were clearly separated from progenitor cells forming colonies in vitro. The present techniques provide suitable numbers of enriched progenitor cells for a variety of biological and biochemical studies.

scholarly journals Abnormal erythroid progenitor cells in human preleukemia

Blood ◽  
1982 ◽  
Vol 60 (2) ◽  
pp. 362-367 ◽  
Author(s):  
DH Chui ◽  
BJ Clarke
Keyword(s):  
Progenitor Cells ◽  
Peripheral Blood ◽  
Culture Technique ◽  
The Other ◽  
Erythroid Cell ◽  
Erythroid Progenitor ◽  
Clonal Culture ◽  
Erythroid Progenitor Cells ◽  
Marrow Cells

Ten patients with preleukemia were studied by the erythroid cell clonal culture technique. In nine of these patients, erythroid colonies derived from peripheral blood BFU-E were not observed, while the other patient had markedly decreased peripheral blood BFU-E-derived erythroid colonies in vitro. In three patients, marrow cells were also cultured and no BFU-E-derived erythroid colonies were detected. These studies indicate that immature erythroid progenitor cells, BFU-E, in patients with preleukemia are either markedly decreased in number or grossly defective in their proliferative or differentiative capacities.

scholarly journals Isolation of murine fetal hemopoietic progenitor cells and selective fractionation of various erythroid precursors

Blood ◽  
1981 ◽  
Vol 58 (2) ◽  
pp. 376-386
Author(s):  
NA Nicola ◽  
D Metcalf ◽  
H von Melchner ◽  
AW Burgess
Keyword(s):  
Progenitor Cells ◽  
Fetal Liver ◽  
Pokeweed Mitogen ◽  
Erythroid Progenitor ◽  
Clonal Proliferation ◽  
Erythroid Progenitor Cells ◽  
Blast Cells ◽  
Hemopoietic Progenitor ◽  
Hemopoietic Progenitor Cells

Hemopoietic progenitor cells (colony- and cluster-forming cells in semisolid agar) were purified from light density CBA murine fetal liver cells using fluorescein-conjugated pokeweed mitogen (PWM) and a rhodamine-conjugated antineutrophil serum sandwich (alpha N) and three- parameter fluorescence-activated cell sorting. All clonable progenitor cells were highly enriched (36–50-fold) in PWM-positive (greater than channel 15), alpha N-negative (less than channel 30) fractions with relatively high intensity (greater than 100) low angle light scatter. No separation was achieved between different types of progenitor cells (granulocyte-macrophage and erythroid colony-forming cells). The enriched fraction was a pure population of large, basophilic, undifferentiated blast cells, and in agar cultures stimulated with colony-stimulating factors, up to 90% of the enriched cells were hemopoietic progenitor cells capable of varying levels of clonal proliferation. Further fractionation based on increasing fluorescence with PWM separated into discrete populations, nonproliferative morphologically recognizable erythroid cells, late erythroid progenitor cells (day 2 CFU-E), and cells forming pure or mixed erythroid burst colonies. In addition, the majority of pluripotential hemopoietic stem cells (CFU-SS) were clearly separated from progenitor cells forming colonies in vitro. The present techniques provide suitable numbers of enriched progenitor cells for a variety of biological and biochemical studies.

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.

Growth and Differentiation of Human Stem Cell Factor/Erythropoietin-Dependent Erythroid Progenitor Cells In Vitro

Blood ◽  
1998 ◽  
Vol 92 (10) ◽  
pp. 3658-3668 ◽  
Author(s):  
Birgit Panzenböck ◽  
Petr Bartunek ◽  
Markus Y. Mapara ◽  
Martin Zenke
Keyword(s):  
Stem Cell ◽  
Progenitor Cells ◽  
Stem Cell Factor ◽  
Large Cell ◽  
Erythroid Cell ◽  
Erythroid Progenitors ◽  
Peripheral Blood Stem Cells ◽  
Erythroid Progenitor ◽  
Cell Numbers

Abstract Stem cell factor (SCF) and erythropoietin (Epo) effectively support erythroid cell development in vivo and in vitro. We have studied here an SCF/Epo-dependent erythroid progenitor cell from cord blood that can be efficiently amplified in liquid culture to large cell numbers in the presence of SCF, Epo, insulin-like growth factor-1 (IGF-1), dexamethasone, and estrogen. Additionally, by changing the culture conditions and by administration of Epo plus insulin, such progenitor cells effectively undergo terminal differentiation in culture and thereby faithfully recapitulate erythroid cell differentiation in vitro. This SCF/Epo-dependent erythroid progenitor is also present in CD34+ peripheral blood stem cells and human bone marrow and can be isolated, amplified, and differentiated in vitro under the same conditions. Thus, highly homogenous populations of SCF/Epo-dependent erythroid progenitors can be obtained in large cell numbers that are most suitable for further biochemical and molecular studies. We demonstrate that such cells express the recently identified adapter protein p62dok that is involved in signaling downstream of the c-kit/SCF receptor. Additionally, cells express the cyclin-dependent kinase (CDK) inhibitors p21cip1 and p27kip1 that are highly induced when cells differentiate. Thus, the in vitro system described allows the study of molecules and signaling pathways involved in proliferation or differentiation of human erythroid cells.

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