Early erythropoiesis in foetal rat bone marrow: evidence for a liver-to-bone marrow relay

Development ◽  
1981 ◽  
Vol 64 (1) ◽  
pp. 275-293
Author(s):  
M. D. Nagel ◽  
J. Nagel ◽  
R. Jacquot
Keyword(s):  
Bone Marrow ◽  
Red Blood Cells ◽  
Blood Cells ◽  
Regulatory Mechanism ◽  
Erythropoietic Activity ◽  
Intrauterine Life ◽  
Foetal Rat ◽  
Stimulate Bone Marrow ◽  
Rat Bone

Erythropoietic activity of foetal rat femoral marrow was examined during the last four days of intra-uterine life. Insignificant at day 18, it develops slowly thereafter until birth. In the non-suckled neonate (not older than two hours), it appears notably enhanced. In order to test the potential of the foetal marrow to develop precocious or increased erythropoiesis, the activity of the erythropoietic organ predominant at this time, the liver, was altered by modifying the level of circulating corticosteroids which govern its function. Maturation and involution of the hepatic erythron were prevented by corticosteroid deprivation of the foetus (maternal adrenalectomy and foetal hypophysectomy). Precocious maturation and exhaustion of the hepatic erythron was induced by submitting foetuses to corticosteroids excess from day 14. Both corticosteroid deprivation and excess increase the erythropoietic activity of the femoral marrow. This activity can reach and even exceed by day 20 of intrauterine life that in neonatal marrow. Foetal hepatic erythron misfunction can therefore initiate and stimulate bone marrow erythropoiesis. The study of circulating red blood cells demonstrates that: (1) anaemia initiates medullary erythropoietic activity; (2) this anaemia is largely corrected by the bone marrow. The regulatory mechanism is presumably erythropoietin mediated.

Normalized levels of red blood cells expressing phosphatidylserine, their microparticles, and activated platelets in young patients with β-thalassemia following bone marrow transplantation

2017 ◽  
Vol 96 (10) ◽  
pp. 1741-1747 ◽  
Author(s):  
Phatchanat Klaihmon ◽  
Sinmanus Vimonpatranon ◽  
Egarit Noulsri ◽  
Surapong Lertthammakiat ◽  
Usanarat Anurathapan ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Red Blood Cells ◽  
Blood Cells ◽  
Marrow Transplantation ◽  
Young Patients ◽  
Activated Platelets

scholarly journals CELLS INVOLVED IN THE IMMUNE RESPONSE

1969 ◽  
Vol 129 (4) ◽  
pp. 757-774 ◽  
Author(s):  
Nabih I. Abdou ◽  
Maxwell Richter
Keyword(s):  
Bone Marrow ◽  
Immune Response ◽  
Red Blood Cells ◽  
Blood Cells ◽  
Bone Marrow Cells ◽  
Allogeneic Bone Marrow ◽  
Red Cells ◽  
Allogeneic Bone ◽  
Sheep Red Blood Cells ◽  
Sheep Red Cells

Irradiated rabbits given allogeneic bone marrow cells from normal adult donors responded to an injection of sheep red blood cells by forming circulating antibodies. Their spleen cells were also capable of forming many plaques using the hemolysis in gel technique, and were also capable of undergoing blastogenesis and mitosis and of incorporating tritiated thymidine upon exposure to the specific antigen in vitro. However, irradiated rabbits injected with allogeneic bone marrow obtained from rabbits injected with sheep red blood cells 24 hr prior to sacrifice (primed donors) were incapable of mounting an immune response after stimulation with sheep red cells. This loss of reactivity by the bone marrow from primed donors is specific for the antigen injected, since the immune response of the irradiated recipients to a non-cross-reacting antigen, the horse red blood cell, is unimpaired. Treatment of the bone marrow donors with high-titered specific antiserum to sheep red cells for 24 hr prior to sacrifice did not result in any diminished ability of their bone marrow cells to transfer antibody-forming capacity to sheep red blood cells. The significance of these results, with respect to the origin of the antigen-reactive and antibody-forming cells in the rabbit, is discussed.

scholarly journals Peripheral Red Blood Cell Split Chimerism as a Consequence of Intramedullary Selective Apoptosis of Recipient Red Blood Cells in a Case of Sickle Cell Disease

2014 ◽  
Vol 6 (1) ◽  
pp. e2014066 ◽  
Author(s):  
Marco Marziali ◽  
Antonella Isgrò ◽  
Pietro Sodani ◽  
Javid Gaziev ◽  
Daniela Fraboni ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Red Blood Cells ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Blood Cells ◽  
Marrow Transplant ◽  
Mixed Chimerism ◽  
Radical Cure ◽  
Hematopoietic Stem ◽  
Hematopoietic Chimerism

Allogeneic cellular gene therapy through hematopoietic stem cell transplantation is the only radical cure for congenital hemoglobinopathies like thalassemia and sickle cell anemia. Persistent mixed hematopoietic chimerism (PMC) has been described in thalassemia and sickle cell anemia. Here, we describe the clinical course of a 6-year-old girl who had received bone marrow transplant for sickle cell anemia. After the transplant, the patient showed 36% donor hematopoietic stem cells in the bone marrow, whereas in the peripheral blood there was evidence of 80%  circulating donor red blood cells (RBC). The analysis of apoptosis at the Bone Marrow  level suggests that Fas might contribute to the cell death of host erythroid precursors. The increase in NK cells and the regulatory T cell population observed in this patient suggests that these cells might contribute to the condition of mixed chimerism.

Red blood cells

2016 ◽  
Author(s):  
Shaun R. McCann
Keyword(s):  
Bone Marrow ◽  
Blood Loss ◽  
Red Blood Cells ◽  
Haemolytic Anaemia ◽  
Blood Cells ◽  
G6pd Deficiency ◽  
Paroxysmal Nocturnal Haemoglobinuria ◽  
Globin Chains ◽  
Glucose 6 Phosphate Dehydrogenase

Red blood cells, erythrocytes, are unique in that they do not contain a nucleus. This fact facilitates the study of their metabolism. Erythrocytes contain the protein pigment haemoglobin, which is in solution in the cells and consists of globin chains and iron. In this chapter, the development of the understanding of erythrocytes is linked to the blood conditions haemolytic anaemia and paroxysmal nocturnal haemoglobinuria. Premature destruction of erythrocytes, in the absence of blood loss, is termed haemolysis. If the bone marrow is unable to compensate adequately, then anaemia ensues and the condition is called haemolytic anaemia. The underlying defect is a deficiency in the activity of the enzyme glucose-6-phosphate dehydrogenase, termed G6PD deficiency.

scholarly journals Physicochemical Properties of Circulating Red Blood Cells of Lethally X-irradiated Mice Treated with Rat Bone Marrow

Blood ◽  
1957 ◽  
Vol 12 (11) ◽  
pp. 984-992 ◽  
Author(s):  
TAKASHI MAKINODAN ◽  
NORMAN G. ANDERSON
Keyword(s):  
Bone Marrow ◽  
Low Temperature ◽  
Physicochemical Properties ◽  
Blood Cells ◽  
Hemoglobin Concentration ◽  
Temperature Dependency ◽  
Molecular Configuration ◽  
Electrophoretic Property ◽  
Osmotic Properties ◽  
Rat Bone

Abstract 1. Two months after injection of rat bone marrow into lethally X-irradiated mice (950 r-RBM mice), 100% of the circulating RBC were serologically of the rat type, indicating that the surface molecular configuration of RBC from these experimental mice are of the rat type. 2. The hemoglobin was found to be also very much like the rat type in its ease in crystallization, its alkali denaturation property, its electrophoretic property, and its tendency to form a paracrystalline state at low temperature. 3. These cells possessed dual osmotic properties; the relative hemoglobin concentration released when cells were lysed in water was more comparable to the rat type, but its temperature dependency was more comparable to the mouse type.

scholarly journals A review of the treatment landscape in paroxysmal nocturnal haemoglobinuria: where are we now and where are we going?

2020 ◽  
Vol 1 ◽  
pp. 263300402095934
Author(s):  
Morag Griffin ◽  
Richard Kelly ◽  
Alexandra Pike
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Life Expectancy ◽  
Red Blood Cells ◽  
Blood Cells ◽  
Treatment Options ◽  
White Blood Cells ◽  
Paroxysmal Nocturnal Haemoglobinuria ◽  
Complement Cascade ◽  
Future Treatments

Paroxysmal nocturnal haemoglobinuria (PNH) is an ultra-orphan disease, which until 15 years ago had limited treatment options. Eculizumab, a monoclonal antibody that inhibits C5 in the terminal complement cascade, has revolutionised treatment for this disease, near normalising life expectancy and improving quality of life for patients. The treatment landscape of PNH is now evolving, with ravulizumab a second longer acting intravenous C5 inhibitor now licenced by the FDA and EMA. With different therapeutic targets in the complement cascade and difference modalities of treatment, including subcutaneous, oral and intravenous therapies being developed, increasing independence for patients and reducing healthcare requirements. This review discusses the current and future therapies for PNH. Lay summary Review of current and future treatments for patients with Paroxysmal Nocturnal Haemoglobinuria What is Paroxysmal Nocturnal Haemoglobinuria? Paroxysmal nocturnal haemoglobinuria (PNH) is a very rare disease. It arises from PNH stem cells in the bone marrow. In a normal bone marrow these are inactive; however, if there has been a problem in the bone marrow, the PNH stem cells can expand and make PNH red blood cells, white blood cells and platelets. The problem with these cells is that they lack the cell surface markers that usually protect them. Red blood cells are broken down in the circulation rather than the spleen, which gives rise to PNH symptoms such as abdominal pain, difficulty swallowing, erectile dysfunction and red or black urine (known as haemoglobinuria). The white blood cells and platelets are ‘stickier’ increasing the risk of blood clots. Previously life expectancy was reduced as there were limited treatment options available. What was the aim of this review? To provide an overview of current and future treatment options for PNH Which treatments are available? • Eculizumab is an treatment given through a vein (intravenous) every week for 5 weeks then every 2 weeks after this, and has been available for 13 years, improving life expectancy to near normal. • Ravulizumab is a newer intravenous treatment similar to eculizumab but is given every 8 weeks instead of every 2 weeks. In clinical studies it was comparable with eculizumab. • Future Treatments - There is new research looking at different methods of treatment delivery, including injections under the skin (subcutaneous) that patients can give themselves, treatments taken by mouth (oral) or a combination of an intravenous and oral treatment for those patients who are not optimally controlled on eculizumab or ravulizumab. What does this mean? PNH is now treatable. For years, the only drug available was eculizumab, but now different targets and drug trials are available. Ravulizumab is currently the only second licenced product available, in USA and Europe, there are other medications active in clinical trials. Why is this important? The benefit for patients, from treatment every 2 weeks to every 8 weeks is likely to be improved further with the development of these new treatments, providing patients with improved disease control and independence. As we move into an era of more patient-friendly treatment options, the PNH community both physicians and patients look forward to new developments as discussed in this article.

The First Trimester Human Placenta Is a Site of Primitive Red Blood Cell Maturation.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2224-2224
Author(s):  
Benjamin J. Van Handel ◽  
Sacha Prashad ◽  
Andy Huang ◽  
Eija Hamalainen ◽  
Angela Chen ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Red Blood Cells ◽  
Human Placenta ◽  
Blood Cells ◽  
Fetal Liver ◽  
First Trimester ◽  
Yolk Sac ◽  
Primitive Hematopoiesis ◽  
Placental Macrophages ◽  
Definitive Erythropoiesis

Abstract Embryonic hematopoiesis occurs in multiple anatomic sites and is generally divided into two waves, primitive and definitive. The primitive wave produces mostly red blood cells in the yolk sac, while the definitive wave generates hematopoietic stem cells (HSCs) that provide lifelong blood homeostasis. Definitive erythropoiesis, occurring first in the fetal liver and eventually the bone marrow, is an orchestrated process in which erythroblasts cluster around a central macrophage. These functional units, termed erythroblast islands, facilitate the maturation of nucleated erythroblasts to enucleated erythrocytes. It has long been thought that primitive red cells maintain their nucleus until undergoing apoptosis; however, the enucleation of primitive erythroblasts has been recently documented in mice, although the site at which this occurs is unknown. We have recently identified the placenta as a major hematopoietic organ that promotes the development of HSCs in mice; preliminary data suggests that the first trimester human placenta also supports definitive hematopoiesis. Surprisingly, our most recent findings indicate a novel, unexpected role for the human placenta in primitive hematopoiesis: the promotion of terminal maturation of primitive erythroblasts. Analysis of placental sections revealed a striking tendency of primitive red blood cells to extravasate from blood vessels in the villi and migrate out into the stroma. Furthermore, once out in the stroma, primitive erythroblasts mature: they lose expression of CD43 and enucleate. The finding that human primitive red blood cells enucleate is undocumented; interestingly, the developmental timing of erythroblast enucleation in humans parallels that in mice. At three weeks, nascent vessels in the placenta are empty, but starting at about 4 weeks, placental circulation begins and fills these vessels with large, nucleated primitive erythroblasts generated in the yolk sac. The migration of primitive erythroblasts into the stroma occurs between 4.5 and 7 weeks. Enucleation mirrors this process, with a large enrichment of enucleated cells in the stroma versus in the vessels at early developmental ages, suggesting that primitive erythroblasts enucleate in the placental stroma. This phenomenon is restricted to placental villi and does not occur in the chorionic plate. Strikingly, extravasated erythroblasts are often in close proximity to placental macrophages, reminiscent of the macrophage-erythroblast associations seen in fetal liver and bone marrow erythropoiesis at later developmental stages. Fetal liver-derived definitive erythrocytes enter circulation at around 8 weeks. After 9–10 weeks, most red blood cells can be observed in vessels, and almost all are enucleated. The concerted processes of extravasation and maturation of primitive erythroblasts in placental stroma nominate the placenta as an important site in primitive hematopoiesis. Furthermore, the association between placental macrophages and primitive erythroblasts suggests that primitive and definitive erythropoiesis share common mechanisms of terminal maturation.

Abnormal Distribution of Erythroid Progenitors Populations in Mice Lacking p45 NF-E2.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1988-1988
Author(s):  
Jadwiga Gasiorek ◽  
Gregory Chevillard ◽  
Zaynab Nouhi ◽  
Volker Blank
Keyword(s):  
Bone Marrow ◽  
Red Blood Cells ◽  
Blood Cells ◽  
Conflicts Of Interest ◽  
Globin Genes ◽  
Erythroid Progenitors ◽  
Erythroid Progenitor ◽  
Adult Mice ◽  
Deficient Mice

Abstract Abstract 1988 Poster Board I-1010 The NF-E2 transcription factor is a heterodimer composed of a large hematopoietic-specific subunit called p45 and widely expressed 18 to 20-kDa small Maf subunits. In MEL (mouse erythroleukemia) cells, a model of erythroid differentiatin, the absence of p45 is inhibiting chemically induced differentiation, including induction of globin genes. In vivo, p45 knockout mice were reported to show splenomegaly, severe thrompocytopenia and mild erythroid abnormalities. Most of the mice die shortly after birth due to haemorrhages. The animals that survive display increased bone, especially in bony sites of hematopoiesis. We confirmed that femurs of p45 deficient mice are filled with bone, thus limiting the space for cells. Hence, we observed a decrease in the number of hematopoietic cells in the bone marrow of 3 months old mice. In order to analyze erythroid progenitor populations we performed flow cytometry using the markers Ter119 and CD71. We found that p45 deficient mice have an increased proportion of early erythroid progenitors (proerythroblasts) and a decreased proportion of late stage differentiated red blood cells (orthochromatic erythroblasts and reticulocytes) in the spleen, when compared to wild-type mice. We showed that the liver of p45 knockout adult mice is also becoming a site of red blood cell production. The use of secondary sites, such as the spleen and liver, suggests stress erythropoiesis, likely compensating for the decreased production of red blood cells in bone marrow. In accordance with those observations, we observed about 2 fold increased levels of erythropoietin in the serum of p45 knockout mice.Overall, our data suggest that p45 NF-E2 is required for proper functioning of the erythroid compartment in vivo. Disclosures: No relevant conflicts of interest to declare.

ACE-536, a Modified Type II Activin Receptor Increases Red Blood Cells In Vivo by Promoting Maturation of Late Stage Erythroblasts

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4236-4236 ◽  
Author(s):  
Rajasekhar NVS Suragani ◽  
Samuel M. Cadena ◽  
Dianne Mitchell ◽  
Dianne Sako ◽  
Monique Davies ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Bone Marrow ◽  
Kidney Disease ◽  
Red Blood Cells ◽  
Late Stage ◽  
Blood Cells ◽  
Treated Group ◽  
Activin A ◽  
Vehicle Group ◽  
Type I

Abstract Abstract 4236 Anemia is one of the most common blood disorders in several diseases including cancer, heart failure, chronic kidney disease (CKD) and Myeloid Dysplastic Syndromes (MDS) associated with a negative outcome. Administration of recombinant Erythropoietin (EPO) represents the most common treatment for anemia. However, a significant number of people remain hypo or non-responsive to EPO treatment, and in some cases its use has been linked to tumor growth, cardiovascular disease and poorer survival. The members of TGFβ super family of ligands (Activins, GDFs and BMPs) and receptors (Type I and II) regulate more than 500 target genes transcriptionally by Smad phosphorylation and are involved in many cellular functions including cell growth, adhesion, migration, differentiation and apoptosis in a concentration and context dependent manner. Members of the TGFβ family have also demonstrated a role in erythropoiesis. ACE-536, a non-ESA agent is a soluble human Fc fusion chimera of a modified Activin Type IIb receptor with a mutation in its extracellular domain. Surface Plasmon Analysis (Biacore) analysis and cell based reporter assays revealed that this mutation disrupted its binding to Activin A but not to GDF11 or GDF8. ACE-536 acts as a decoy receptor for TGFβ signaling and demonstrated potent increase in red blood cells in all the tested animals (mice, rats and monkeys). Subcutaneous administration of ACE-536 (10mg/kg) to C57BL/6 mice resulted in a significant increase in hematocrit, hemoglobin and red blood cells (RBC) over the TBS treated vehicle group after 4 days. These observations were seen even in the presence of an EPO neutralizing antibody; suggesting that EPO is not directing the initial RBC response to ACE-536 treatment. There were no increase in BFU-E or CFU-E colony formation from bone marrow and spleen after 48hrs treatment with ACE-536 over TBS treated group demonstrating that it does not have effect on erythroid progenitor population. Differentiation profiling of bone marrow and splenic erythroblasts by flow cytometric analysis revealed that ACE-536 promotes maturation of developing erythroblasts. ACE-536 treatment for 72 hours resulted in a decrease in basophilic erythroblasts and an increase in late stage poly, ortho chromatophilic erythroblasts in bone marrow and spleen compared to the TBS treated mice. Treatment of Sprague-Dawley rats with a murine analogue of ACE-536 (RAP-536; 10mg/kg) increased the reticulocyte formation in peripheral blood over vehicle treated group. ACE-536 (10mg/kg) treatment combined with recombinant human EPO (1800 units/kg) for 72 hours increased RBC, hematocrit and hemoglobin by approximately 23% over TBS treated vehicle group and 12% over EPO treatment alone. Consistent with its role in proliferation, EPO increased splenic basophilic erythroblast formation. However, ACE-536 treatment combined with EPO significantly promoted maturation of late stage erythroblasts; demonstrating a novel mechanism during erythroid differentiation. To gain further insights into its mechanism of action, C57BL/6 mice were administered with or without RAP-536 (10mg/ml twice a week) pre treated for a week with neutralizing anti-Activin A (10mg/kg) or ActRIIa (10mg/ml) or ActRIIb (10mg/ml) (does not bind ACE-536) antibodies. Anti-ActRIIa but not anti-Activin A or anti- ActRIIb antibody pre-treatment inhibited the RBC increase by RAP-536 suggesting that ActRIIa or its ligands are necessary for transducing the signal. To summarize, ACE-536 treatment results in a rapid increase in red blood cells by a novel mechanism promoting maturation of late stage erythroblasts. The efficacy of ACE-536 molecule was tested in several acute and chronic anemia animal models including blood loss anemia, chemotherapy induced anemia, chronic kidney disease (5/6 Nephrectomy) and Myeloid Dysplastic Syndrome (MDS) and found that ACE-536 treatment prevents or decreases anemia in all these models. Furthermore, unlike EPO, ACE-536 did not promote tumor progression (in Lewis Lung Carcinoma model) thus offering strong promise as alternate treatments for anemia. Disclosures: Suragani: Acceleron Pharma: Employment. Cadena:Acceleron Pharma: Employment. Mitchell:Acceleron Pharma: Employment. Sako:Acceleron Pharma: Employment. Davies:Acceleron Pharma: Employment. Tomkinson:Acceleron Pharma: Employment. Devine:Acceleron Pharma: Employment. Ucran:Acceleron Pharma: Employment. Grinberg:Acceleron Pharma: Employment. Underwood:Acceleron Pharma: Employment. Pearsall:Acceleron Pharma: Employment. Seehra:Acceleron Pharma: Employment. Kumar:Acceleron Pharma: Employment.

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