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PubMed1990

A mathematical model of erythropoiesis suggests an altered plasma volume control as cause for anemia in aged mice.

In order to evaluate whether the anemia observed in aged C57B1 and B6D2F1 mice reflects a defect in the control mechanisms regulating erythropoiesis a mathematical model of erythropoietic control is employed, validated previously. In the model it is hypothesized that the most important mechanism for compensating an actual demand of red blood cells is an increase in the mitotic amplification (number of mitoses) of erythroid progenitors (CFU-E, erythroblasts). The same sigmoidal dose-response-relationship between mitotic amplification and hematocrit (Hct) is proposed for young and aged mice. It is mediated by erythropoietin (EPO). Using this relationship one can demonstrate that the expansion of the plasma volume (PV) observed in aged mice is appropriately compensated by an increase in the mitotic amplification of CFU-E and erythroblasts. This implies that aged mice operate in a stimulated state of erythropoietic amplification which is closer to the maximum of the dose-response-relationship than the steady state in young mice. This explains the finding of a reduced proliferative reserve in aged mice following further erythropoietic stimulation. An additional analysis regarding the response of aged mice to bleeding anemia is consistent with the view that young and aged mice share the same dose-response-relationship but start from different steady states. These findings suggest that the control mechanisms regulating erythropoiesis in young and aged mice are similar and that the anemia is due to alterations in the PV control.

Animals↗

PubMed2006

Animal models with enhanced erythropoiesis and iron absorption.

The regulation of iron absorption is of considerable interest in mammals since excretion is minimal. Recent advances in iron metabolism have expounded the molecular mechanisms by which iron absorption is attuned to the physiological demands of the body. The pinnacle was the discovery and identification of hepcidin, a hepatic antimicrobial peptide that regulates absorption to maintain iron homeostasis. While the intricacies of its expression and regulation by HFE, transferrin receptor 2 and hemojuvelin are still speculative, hepcidin responsiveness has correlated negatively with iron absorption in different models and disorders of iron metabolism. Consequently, hepcidin expression is repressed to enhance iron absorption during stimulated erythropoiesis even in situations of elevated iron stores. Animal models have been crucial to the advances in understanding iron metabolism and the present review focuses on phenylhydrazine treated and hypotransferrinaemic rodents. These, respectively, experimental and genetic models of enhanced erythropoiesis highlight the shifting focus of iron absorption regulation from the marrow to the liver.

Anemia, Hemolytic↗

PubMed2006

Dexamethasone facilitates erythropoiesis in murine embryonic stem cells differentiating into hematopoietic cells in vitro.

Differentiating embryonic stem (ES) cells are increasingly emerging as an important source of hematopoietic progenitors with a potential to be useful for both basic and clinical research applications. It has been suggested that dexamethasone facilitates differentiation of ES cells towards erythrocytes but the mechanism responsible for sequential expression of genes regulating this process are not well-understood. Therefore, we in vitro induced differentiation of murine ES cells towards erythropoiesis and studied the sequential expression of a set of genes during the process. We hypothesized that dexamethasone-activates its cognate nuclear receptors inducing up-regulation of erythropoietic genes such as GATA-1, Flk-1, Epo-R, and direct ES cells towards erythropoietic differentiation. ES cells were cultured in primary hematopoietic differentiation media containing methyl-cellulose, IMDM, IL-3, IL-6, and SCF to promote embryoid body (EB) formation. Total RNA of day 3, 5, and 9-old EBs was isolated for gene expression studies using RT-PCR. Cells from day 9 EBs were subjected to secondary differentiation using three different cytokines and growth factors combinations: (1) SCF, EPO, dexamethasone, and IGF; (2) SCF, IL-3, IL-6, and TPO; and, (3) SCF IL-3, IL-6, TPO, and EPO. Total RNA from day 12 of secondary differentiated ES cells was isolated to study the gene expression pattern during this process. Our results demonstrate an up-regulation of GATA-1, Flk-1, HoxB-4, Epo-R, and globin genes (alpha-globin, betaH-1 globin, beta-major globin, epsilon -globin, and zeta-globin) in the 9-day-old EBs, whereas, RNA from 5-day-old EBs showed expression of HoxB-4, epsilon-globin, gamma-globin, betaH1-globin, and Flk-1. Three-day-old EBs showed only HoxB-4 and Flk-1 gene expression and lacked expression of all globin genes. These findings indicate that erythropoiesis-specific genes are activated later in the course of differentiation. Gene expression studies on the ES cells of secondary EB origin cultured in media containing dexamethasone showed a down-regulation of GATA-3 and an up-regulation of GATA-1, Flk-1, and Epo-R in comparison to the two other cytokines and growth factor combinations containing media. The secondary differentiation also showed an enhanced production of erythrocytic precursors in dexamethasone containing media in comparison to that in the control media. Our results indicate that dexamethasone can prove to be an effective agent which can be employed to enhance differentiation towards erythrocytic progenitors from ES cells.

Animals↗

PubMed2006

Carbamylated erythropoietin protects the kidneys from ischemia-reperfusion injury without stimulating erythropoiesis.

Several studies have shown that erythropoietin (EPO) can protect the kidneys from ischemia-reperfusion injury and can raise the hemoglobin (Hb) concentration. Recently, the EPO molecule modified by carbamylation (CEPO) has been identified and was demonstrated to be able to protect several organs without increasing the Hb concentration. We hypothesized that treatment with CEPO would protect the kidneys from tubular apoptosis and inhibit subsequent tubulointerstitial injury without erythropoiesis. The therapeutic effect of CEPO was evaluated using a rat ischemia-reperfusion injury model. Saline-treated kidneys exhibited increased tubular apoptosis with interstitial expression of alpha-smooth muscle actin (alpha-SMA), while EPO treatment inhibited tubular apoptosis and alpha-SMA expression to some extent. On the other hand, CEPO-treated kidneys showed minimal tubular apoptosis with limited expression of alpha-SMA. Moreover, CEPO significantly promoted tubular epithelial cell proliferation without erythropoiesis. In conclusion, we identified a new therapeutic approach using CEPO to protect kidneys from ischemia-reperfusion injury.

Animals↗

PubMed2005

In vitro dual effect of arsenic trioxide on hemopoiesis: inhibition of erythropoiesis and stimulation of megakaryocytic maturation.

Although the arsenic compounds are now widely utilized in clinics in the treatment of various tumors, their effects on normal hematopoiesis do not seem to have been explored. In the present study, we provide evidence that arsenic trioxide (As(2)O(3)) exerts in vitro a potent inhibitory effect on normal erythropoiesis and a stimulatory action on megakaryocytic differentiation. The effect of As(2)O(3) on erythroid and megakaryocytic differentiation was evaluated on both erythroleukemic cell lines K562 and HEL and on normal hemopoietic progenitor cells (HPCs) induced to selective erythroid or megakaryocytic differentiation. The inhibitory effect of As(2)O(3) on erythropoiesis is related to: (a) the inhibition of Stat5 activation with consequent reduced expression of the target genes Bcl-X(L) and glycophorin-A; (b) the activation of an apoptotic mechanism that leads to the cleavage of the erythroid transcription factors Tal-1 and GATA-1, whose integrity is required for erythroid cell survival and differentiation; (c) the reduced expression of heat shock protein 70, required for GATA-1 integrity. The stimulatory effect of As(2)O(3) on normal megakaryocytopoiesis is seemingly related to upmodulation of GATA-2 expression and to stimulation of MAPK activity. These observations may have implications for the patients undergoing anti-leukemic treatment with this compound.

Antineoplastic Agents↗

PubMed2006

Erythropoiesis in the Rps19 disrupted mouse: Analysis of erythropoietin response and biochemical markers for Diamond-Blackfan anemia.

The human ribosomal protein S19 gene (RPS19) is mutated in approximately 20% of patients with Diamond-Blackfan anemia (DBA), a congenital disease with a specific defect in erythropoiesis. The clinical expression of DBA is highly variable, and subclinical phenotypes may be revealed by elevated erythrocyte deaminase (eADA) activity only. In mice, complete loss of Rps19 results in early embryonic lethality whereas Rps19+/- mice are viable and without major abnormalities including the hematopoietic system. We have performed a detailed analysis of the Rps19+/- mice. We estimated the Rps19 levels in hematopoietic tissues and we analyzed erythrocyte deaminase activity and globin isoforms which are used as markers for DBA. The effect of a disrupted Rps19 allele on a different genetic background was investigated as well as the response to erythropoietin (EPO). From our results, we argue that the loss of one Rps19 allele in mice is fully compensated for at the transcriptional level with preservation of erythropoiesis.

Anemia, Diamond-Blackfan↗

PubMed2006

Identification of tenascin-C as a key molecule determining stromal cell-dependent erythropoiesis.

OBJECTIVE: We previously established 33 bone marrow stromal cell lines from SV40 T-antigen transgenic mice. Of these, 27 clones supported erythroid colony formation, while 6 did not. The objective of this study is to identify the molecules that determine these erythroid colony-forming activities. MATERIALS AND METHODS: We compared gene expression profiling by DNA microarray between cell lines that support erythropoiesis (E(+); TBR9, 184, 31-2) and cell lines that do not (E(-); TBR17, 33, 511). Among the differentially expressed genes, we selected candidate genes with results of quantitative reverse transcriptase polymerase chain reaction, and examined the effect of small interfering RNA (siRNA) and the addition of exogenous proteins on the erythroid colony formation. RESULTS: Out of 7226 genes examined, 138 and 282 genes were upregulated and downregulated in E(+) by threefold or more, respectively. We have selected one of the upregulated genes, tenascin-C (TN-C), as a candidate. Expressions of TN-C in E(+) were all higher than the three E-cell lines, with a mean of 3.6-fold. The number of erythroid colonies in the presence of TN-C siRNA was significantly lower than that of control siRNA in TBR9 (20.7 +/- 6.3 vs 4.7 +/- 4.8 colonies; p = 0.01) and in TBR184 (13.3 +/- 5.3 vs 0.3 +/- 0.5; p = 0.02). Moreover, addition of exogenous TN-C enhanced the number of erythroid colonies in TBR184 (13.3 +/- 3.5 vs 20.0 +/- 2.0; p = 0.04) and in TBR31-2 (7.5 +/- 3.1 vs 13.5 +/- 2.6; p = 0.03). CONCLUSION: These results suggest that TN-C is responsible for determining the stromal cell-dependent erythropoiesis.

Animals↗

PubMed2006

Heat shock protein 70 inhibits the nuclear import of apoptosis-inducing factor to avoid DNA fragmentation in TF-1 cells during erythropoiesis.

Loss of mitochondrial membrane potential (DeltaPsi(m)) and release of AIF (apoptosis-inducing factor) from mitochondria are key steps in apoptosis. In TF-1 model, DeltaPsi(m) was depolarized with AIF release during erythroid development. Yet, no DNA fragmentation was observed. When DeltaPsi(m) depolarization had been blocked, erythropoiesis was suppressed. Interestingly, heat shock protein 70 (Hsp70) was found transiently upregulated during depolarization and it retained AIF in the cytosol to avoid DNA damages. When Hsp inhibitor was added, DNA fragmentation occurred. We show this mechanism for the first time in erythropoiesis how cells with DeltaPsi(m) depolarization and AIF release escape apoptosis.

Apoptosis Inducing Factor↗

PubMed2004

Malarial anaemia: mechanisms and implications of insufficient erythropoiesis during blood-stage malaria.

It has been proposed that the basis of severe malarial anaemia, a major cause of morbidity and mortality in endemic areas, is multifactorial. Inappropriately low reticulocytosis is observed in malaria patients suggesting that insufficient erythropoiesis is a major factor. Clinical studies provide conflicting data concerning the production of adequate levels of erythropoietin (EPO) during malaria. Plasmodium chabaudi AS causes non-lethal infection in resistant C57BL/6 mice, and lethal infection in susceptible A/J mice. In P. chabaudi AS infected C57BL/6 and A/J mice, which experience varying degrees of severity of anaemia, kidney EPO production is appropriate to the severity of anaemia and is regulated by haematocrit level. Neutralisation of endogenous EPO during infection leads to lethal anaemia while timely administration of exogenous EPO rescues mice although reticulocytosis is suppressed in proportion to the parasitemia level. Characterisation of alterations in splenic erythroid compartments in naive and P. chabaudi AS infected A/J mice revealed that infection, with or without EPO treatment, leads to sub-optimal increases in TER119+ erythroblasts compared to EPO-treated naive mice. A lower percentage of TER119+ erythroblasts in infected mice undergo terminal differentiation to become mature haemoglobin-producing cells. Furthermore, there is a shift in transferrin receptor (CD71) expression from TER119+ cells to a non-erythroid population. Deficiencies in the number and maturation of TER119+ erythroblasts during infection coincide with blunted proliferation to EPO stimulation in vitro by splenocytes, although a high frequency express EPO receptor (EPOR). Together, these data suggest that during malaria, EPO-induced proliferation of early EPOR+ erythroid progenitors is suppressed, leading to sub-optimal generation of TER119+ erythroblasts. Moreover, a shift in CD71 expression may result in impaired terminal maturation of erythroblasts. Thus, suppressed proliferation, differentiation, and maturation of erythroid precursors in association with inadequate reticulocytosis may be the basis of insufficient erythropoiesis during malaria.

Anemia↗

PubMed2006

Dialysis adequacy and response to erythropoiesis-stimulating agents: what is the evidence base?

Despite an increase in the use and average dose of erythropoiesis-stimulating agents (ESA) over the past 15 years, a substantial percentage of patients still do not achieve hemoglobin targets recommended by international guidelines. A clear relationship among hemoglobin or hematocrit levels, ESA dose, and increase in dialysis dose has been pointed out by a number of prospective or retrospective studies. This is particularly true in patients receiving inadequate dialysis. Increasing attention also has been paid to the relationship between dialysis, increased inflammatory stimulus, and ESA response because dialysate contamination and low-compatible treatments may increase cytokine production and consequently inhibit erythropoiesis. The biocompatibility of dialysis membranes and flux are other important factors. However, in highly selected, adequately dialyzed patients without iron or vitamin depletion, the effect of these treatment modalities on anemia seems to be smaller than expected. The role of on-line treatments still is controversial given that it is still difficult to discriminate between the effect of on-line hemodiafiltration per se from that of an increased dialysis dose. Very preliminary results obtained with short or long nocturnal daily hemodialysis on anemia correction are encouraging.

Anemia↗

PubMed1995

Erythropoiesis, erythropoietin, and iron metabolism in elective surgery: preoperative strategies for avoiding allogeneic blood exposure.

Preoperative autologous donation (PAD) of blood and administration of recombinant human erythropoietin (Epoetin alfa) are two strategies for increasing red blood cell (RBC) mass preoperatively. The success of PAD depends primarily on the patient's ability to manufacture new RBCs before surgery to replace those removed during PAD. Red blood cell manufacture depends in turn on adequate supplies of iron and the increased renal production of endogenous erythropoietin following PAD. Successful PAD also requires adequate time for regeneration of predonated RBCs. Parenteral administration of Epoetin alfa causes a dose-dependent stimulation of RBC production. Its use has been studied as an adjunct to PAD and as a method to enhance endogenous erythropoiesis without PAD. Several studies suggest that administration of Epoetin alfa, begun several days before surgery, may stimulate erythropoiesis and help decrease the number of RBC transfusions required postoperatively. The precise role of Epoetin alfa in the surgical setting is not yet established, and optimal dosage regimens have not been determined.

Aged↗

PubMed2002

A role of EphB4 receptor and its ligand, ephrin-B2, in erythropoiesis.

Erythropoiesis is regulated not only by erythropoietin but also by microenvironments which are composed of transmembrane molecules. We have previously shown that a receptor tyrosine kinase EphB4 is predominantly expressed on human erythroid progenitors in bone marrow. EphB4 is expressed in approximately 45% of hematopoietic progenitor cells, which are CD34-positive and c-Kit-positive in human umbilical cord blood (hUCB). The transmembrane ligand for EphB4 or ephrin-B2 is expressed on bone marrow stromal cells and arterial endothelial cells. When such EphB4-positive hematopoietic progenitor cells were co-cultured with stromal cells which express ephrin-B2, they were immediately detached from stromal cells and differentiated to mature erythroid cells. At that time, expression of EphB4 immediately down-regulated. In contrast, on ephrin-B2 non-expressing stromal cells, they remained EphB4-positive cells and the generated number of mature erythroid cells was less than that on ephrin-B2 expressing stromal cells. Additionally, ephrin-B2 expression on endothelial cells up-regulated under hypoxic condition. Taken together, we propose that one of the molecular cues that regulate erythropoiesis is ephrin-B2 on stromal cells.

Cell Division↗

PubMed1990

Effects of intravascular, intrauterine transfusion on prenatal and postnatal hemolysis and erythropoiesis in severe fetal isoimmunization.

In an investigation of the effects of intrauterine, intravascular transfusions (IUT) on fetal and neonatal hemolysis and erythropoiesis, 12 fetuses who received IUT for treatment of severe isoimmunization had serial measurements of hemoglobin concentration, Kleihauer-Betke stains to detect fetal hemoglobin-containing erythrocytes, and determination of plasma erythropoietin (EPO) concentration before each IUT, at birth, and postnatally. Reticulocyte counts and sensitizing antibody titers were measured in five fetuses. Mean values before the first IUT, before the final IUT, and at birth were as follows: hemoglobin level, 6.1, 9.1, and 11.3 gm/dl; reticulocyte count, 22.7%, 0.5%, and 0.9%; fetal hemoglobin-containing erythrocytes, 100%, 1.6%, and 1.5%; and EPO level, 12, 56, and 756 mU/ml, respectively. Only one neonate required exchange transfusion. In the first month postnatally, all infants had a profound anemia. All but one infant required simple blood transfusions postnatally. Before the first postnatal transfusion, mean hemoglobin concentration was 6.2 gm/dl, mean reticulocyte count was 0.8%, mean erythropoietin concentration was 23 mU/ml, and the sensitizing antibody titer remained markedly elevated. Except for the surge of EPO at birth, EPO levels did not rise prenatally or postnatally unless marked anemia (hemoglobin level less than 5 gm/dl) occurred. These observations suggest that the intrauterine and postnatal anemia in fetuses who receive IUTs may be explained both by hemolysis of newly formed erythrocytes by circulating antibody, which typically persisted for more than a month after birth, and by suppressed erythropoiesis.

Anemia, Neonatal↗

PubMed1992

Regulation of erythropoiesis. The role of growth factors.

Erythropoiesis involves a cascade of differentiation steps that are driven by a variety of glycoproteins. The authors discuss erythropoietin, interleukin-3, and granulocyte macrophage colony-stimulating factor, the best understood of the growth factors regulating erythropoiesis, as well as tumor necrosis factor and other cytokines.

Erythropoiesis↗

PubMed1991

A B cell line from a patient with pure red cell aplasia produces an immunoglobulin that suppresses erythropoiesis.

A 4-year-old boy with pure red cell aplasia was investigated. Immunophenotypic analysis of peripheral blood lymphocytes revealed a marked increase of CD20+ cells, which fell from 25.9% in the active stage to 9.7% in remission. The plasma contained a suppressive activity against CFU-e and BFU-e formation by the patient's bone marrow cells, which disappeared when the disease went into remission. Prednisone (2 mg/kg/day) therapy was tried for 5 weeks, but produced no improvement. Subsequently, high-dose gamma-globulin therapy induced complete remission of anemia. A lymphoblastoid B cell line obtained from the patient before therapy produced a factor that suppressed erythropoiesis but not granulopoiesis. The suppressive activity resided in the immunoglobulin fraction and was adsorbed by an anti-immunoglobulin column. These results indicate that expansion of B cells producing an immunoglobulin which suppressed erythropoiesis was involved in the pathogenesis of the disease in this patient.

B-Lymphocytes↗

PubMed2000

Requirement for p38alpha in erythropoietin expression: a role for stress kinases in erythropoiesis.

Activity of the p38alpha MAP kinase is stimulated by various stresses and hematopoietic growth factors. A role for p38alpha in mouse development and physiology was investigated by targeted disruption of the p38alpha locus. Whereas some p38alpha(-/-) embryos die between embryonic days 11.5 and 12.5, those that develop past this stage have normal morphology but are anemic owing to failed definitive erythropoiesis, caused by diminished erythropoietin (Epo) gene expression. As p38alpha-deficient hematopoietic stem cells reconstitute lethally irradiated hosts, p38alpha function is not required downstream of Epo receptor. Inhibition of p38 activity also interferes with stabilization of Epo mRNA in human hepatoma cells undergoing hypoxic stress. The p38alpha MAP kinase plays a critical role linking developmental and stress-induced erythropoiesis through regulation of Epo expression.

Anemia↗

PubMed1999

SOCS3 is essential in the regulation of fetal liver erythropoiesis.

SOCS3 (CIS3/JAB2) is an SH2-containing protein that binds to the activation loop of Janus kinases, inhibiting kinase activity, and thereby suppressing cytokine signaling. During embryonic development, SOCS3 is highly expressed in erythroid lineage cells and is Epo independent. Transgene-mediated expression blocks fetal erythropoiesis, resulting in embryonic lethality. SOCS3 deletion results in an embryonic lethality at 12-16 days associated with marked erythrocytosis. Moreover, the in vitro proliferative capacity of progenitors is greatly increased. SOCS3-deficient fetal liver stem cells can reconstitute hematopoiesis in lethally irradiated adults, indicating that its absence does not disturb bone marrow erythropoiesis. Reconstitution of lymphoid lineages in JAK3-deficient mice also occurs normally. The results demonstrate that SOCS3 is critical in negatively regulating fetal liver hematopoiesis.

Animals↗

PubMed1997

Possible involvement of protein kinase C in the aberrant regulation of erythropoiesis in polycythemia vera.

To examine the possible involvement of protein kinase C (PKC) in the regulation of aberrant erythropoiesis of polycythemia vera (PV), we investigated the effects of PKC inhibitors on in vitro burst-forming unit of erythroid (BFU-E)-derived colony formation by bone marrow (BM) and peripheral blood (PB) cells obtained from five PV patients. 1-(Isoquinoline-sulfonyl)-2-methylpiperazine dihydrochloride (H-7), an inhibitor of PKC, suppressed the colony formation by BM and PB cells of PV patients in a dose-dependent manner, similar to those in the normal individuals. However, the 50% inhibitory concentrations (IC50) of H-7 in PV BM and PB cells were significantly higher than those in normal BM and PB cells, respectively. The BFU-E-derived colony formation by PV BM and PB cells was also less affected by Staurosporine, another PKC inhibitor, than those in a normal subject. Furthermore, in the study of PV, the IC50 of endogenous colonies formed in the absence of erythropoietin was much higher than that of colonies formed by the stimulation of erythropoietin. By contrast, N-(2-guanidinoethyl)-5-isoquinolinesulfonamide dihydrochloride (HA1004), a cyclic AMP-dependent kinase inhibitor, did not have such inhibitory effects. These findings suggest that PKC, as a second messenger, is involved in the regulation of aberrant erythropoiesis of PV.

Adult↗