RESUMEN
Under normal conditions, iron metabolism is carefully regulated to sustain normal cellular functions and the production of hemoglobin in erythroid cells. Perturbation to the erythropoiesis-iron metabolism axis can result in iron imbalances and cause anemia or organ toxicity. Various congenital and acquired diseases associated with abnormal red cell production are characterized by aberrant iron absorption. Several recent studies have shown that improvements in red blood cell production also ameliorate iron metabolism and vice versa. Many therapeutics are now under development with the potential to improve a variety of hematologic diseases, from ß-thalassemia and iron-refractory iron deficiency anemia to anemia of inflammation and polycythemia vera. This review summarizes selected mechanisms related to red cell production and iron metabolism and describes potential therapeutics and their current uses. We also consider the potential application of the discussed therapeutics on various diseases, alone or in combination. The vast repertoire of drugs under development offers new opportunities to improve the clinical care of patients suffering from congenital or acquired red blood cell disorders with limited or no treatment options.
Asunto(s)
Anemia Ferropénica , Enfermedades Hematológicas , Talasemia beta , Humanos , Eritropoyesis , Eritrocitos/metabolismo , Hierro/metabolismo , Talasemia beta/metabolismo , Enfermedades Hematológicas/tratamiento farmacológicoRESUMEN
Sickle cell disease (SCD) is an inherited blood disorder caused by a ß-globin gene point mutation that results in the production of sickle hemoglobin that polymerizes upon deoxygenation, causing the sickling of red blood cells (RBCs). RBC deformation initiates a sequence of events leading to multiple complications, such as hemolytic anemia, vaso-occlusion, chronic inflammation, and tissue damage. Macrophages participate in extravascular hemolysis by removing damaged RBCs, hence preventing the release of free hemoglobin and heme, and triggering inflammation. Upon erythrophagocytosis, macrophages metabolize RBC-derived hemoglobin, activating mechanisms responsible for recycling iron, which is then used for the generation of new RBCs to try to compensate for anemia. In the bone marrow, macrophages can create specialized niches, known as erythroblastic islands (EBIs), which regulate erythropoiesis. Anemia and inflammation present in SCD may trigger mechanisms of stress erythropoiesis, intensifying RBC generation by expanding the number of EBIs in the bone marrow and creating new ones in extramedullary sites. In the current review, we discuss the distinct mechanisms that could induce stress erythropoiesis in SCD, potentially shifting the macrophage phenotype to an inflammatory profile, and changing their supporting role necessary for the proliferation and differentiation of erythroid cells in the disease. The knowledge of the soluble factors, cell surface and intracellular molecules expressed by EBI macrophages that contribute to begin and end the RBC's lifespan, as well as the understanding of their signaling pathways in SCD, may reveal potential targets to control the pathophysiology of the disease.
Asunto(s)
Anemia de Células Falciformes , Linfohistiocitosis Hemofagocítica , Humanos , Eritropoyesis , Eritrocitos , Macrófagos/metabolismo , Inflamación/metabolismoRESUMEN
ABSTRACT The development of red blood cells (RBCs), or erythropoiesis, occurs in specialized niches in the bone marrow, called erythroblastic islands, composed of a central macrophage surrounded by erythroblasts at different stages of differentiation. Upon anemia or hypoxemia, erythropoiesis extends to extramedullary sites, mainly spleen and liver, a process known as stress erythropoiesis, leading to the expansion of erythroid progenitors, iron recruitment and increased production of reticulocytes and mature RBCs. Macrophages are key cells in both homeostatic and stress erythropoiesis, providing conditions for erythroid cells to survive, proliferate and differentiate. During RBCs aging and injury, macrophages play a fundamental role again, performing the clearance of these cells and recycling iron for new erythroblasts in development. Thus, macrophages are crucial components of the RBCs turnover and in this review, we aimed to cover the main known mechanisms involved in the process of birth and death of RBCs, highlighting the importance of macrophage functions in the whole RBC lifecycle.
Asunto(s)
Eritrocitos , Macrófagos , EritropoyesisRESUMEN
BACKGROUND: The presence of Plasmodium vivax malaria parasites in the human bone marrow (BM) is still controversial. However, recent data from a clinical case and experimental infections in splenectomized nonhuman primates unequivocally demonstrated the presence of parasites in this tissue. METHODS: In the current study, we analyzed BM aspirates of 7 patients during the acute attack and 42 days after drug treatment. RNA extracted from CD71+ cell suspensions was used for sequencing and transcriptomic analysis. RESULTS: We demonstrated the presence of parasites in all patients during acute infections. To provide further insights, we purified CD71+ BM cells and demonstrated dyserythropoiesis and inefficient erythropoiesis in all patients. In addition, RNA sequencing from 3 patients showed that genes related to erythroid maturation were down-regulated during acute infections, whereas immune response genes were up-regulated. CONCLUSIONS: This study thus shows that during P. vivax infections, parasites are always present in the BM and that such infections induced dyserythropoiesis and ineffective erythropoiesis. Moreover, infections induce transcriptional changes associated with such altered erythropoietic response, thus highlighting the importance of this hidden niche during natural infections.
Asunto(s)
Anemia , Malaria Vivax , Animales , Médula Ósea , Eritropoyesis , Humanos , Malaria Vivax/parasitología , Plasmodium vivax/genéticaRESUMEN
Abstract Introduction: In amphibians, blood may act as a hematopoietic tissue. However, the knowledge concerning hematological features is scarce, there is not much information that allows an analysis about the possible explanations of this physiological feature. Objective: This study aimed to evaluate the relationship between immature red blood cells (RBCs) mitosis and the presence of blood parasites in amphibians. Methods: We sampled 116 amphibians (31 species) in six Colombian localities. Blood was taken by cardiac puncture or maxillary vein puncture. Smears were prepared, fixed, and Giemsa stained for microscopical analysis. The variables analyzed were the percentage of immature RBCs, mitotic cells in peripheral blood, and blood parasite infection. Data were analyzed using Wilcoxon's rank test and exact Fisher statistical tests. Results: Sixty-two individuals showed mitosis in peripheral blood, and these mitotic RBCs shared morphological features with immature RBCs. Overall, parasite prevalence was 30.1 %, distributed as follows: Trypanosoma (24.1 %), Hepatozoon-like (6 %), Dactylosoma (4.3 %), Karyolysus-like (0.9 %), and Filarioidea (2.6 %). A positive association between the percentage of immature RBCs and the presence of mitotic RBCs was found, and also between the blood parasite infection and the percentage of immature RBCs. Conclusions: In this study, we found that the presence of blood parasites, immature RBCs, and RBCs mitosis are frequent events in amphibians' peripheral blood, and our analysis suggests an association between those features. Thus, the release of immature RBCs and the mitosis of those cells in peripheral blood may be a physiological response to blood parasite infection. Further studies characterizing hematology in amphibians and wildlife, in general, are desirable.
Resumen Introducción: En anfibios, la sangre puede actuar como un tejido hematopoyético. Sin embargo, el conocimiento acerca de las características hematológicas es escaso y no hay información que permita un análisis acerca de las posibles explicaciones a este rasgo fisiológico. Objetivo: La intención de este estudio fue evaluar la relación entre la presencia de eritroblastos, mitosis de glóbulos rojos (GRs) y la infección por hemoparásito en sangre periférica de anfibios. Métodos: Se muestrearon 116 anfibios (31 especies) en seis localidades de Colombia. Se tomaron muestras de sangre mediante punción cardiaca o punción a la vena maxilar. Se prepararon extendidos sanguíneos, se fijaron y tiñeron con Giemsa para su posterior análisis por microscopía. Se analizaron variables como porcentaje de GRs inmaduros, células mitóticas en sangre periférica e infección por hemoparásitos. Los datos fueron analizados mediante el test de rango de Willcoxon y el test exacto de Fisher. Resultados: sesenta y dos individuos evidenciaron mitosis en sangre periférica y dichas mitosis compartían características morfológicas con GRs inmaduros. La prevalencia general de parásitos fue del 30.1 %, distribuido de la siguiente forma: Trypanosoma (24.1 %), Hepatozoon-like (6 %), Dactylosoma (4.3 %), Karyolysus-like (0.9 %), y Filarioidea (2. 6 %). Hay una asociación positiva entre el porcentaje de GRs inmaduros y la presencia de células mitóticas, también se encontró una relación entre la infección por hemoparásitos y el porcentaje de GRs inmaduros. Conclusiones: En este estudio encontramos que la presencia de parásitos sanguíneos, GRs inmaduros y mitosis de GRs son eventos frecuentes en sangre periférica de anfibios, y nuestros resultados sugieren una asociación entre dichas características. Por tanto, la liberación de GRs inmaduros y la mitosis de estas células en sangre periférica podría ser una respuesta fisiológica a infecciones parasitarias. Posteriores estudios que caractericen la hematología en anfibios y en vida silvestre en general, son deseables.
Asunto(s)
Animales , Parásitos/patogenicidad , Anfibios/sangre , Eritropoyesis , AnemiaRESUMEN
NEW FINDINGS: What is the central question of this study? To what extent does testosterone influence haemoglobin formation during male puberty? What is the main finding and its importance? In boys, testosterone might be responsible for about 65% of the increase in haemoglobin mass during puberty. The underlying mechanisms are assumed to be twofold: (i) indirectly, mediated by the increase in lean body mass, and (ii) directly by immediate testosterone effects on erythropoiesis. Thereby, an increase in testosterone of 1 ng/ml is associated with an increase in haemoglobin mass of â¼65 g. These processes are likely to determine endurance performance in adulthood. ABSTRACT: The amount of haemoglobin during puberty is related to endurance performance in adulthood. During male puberty, testosterone stimulates erythropoiesis and could therefore be used as a marker for later endurance performance. This cross-sectional study aimed to determine the relationship between serum testosterone concentration and haemoglobin mass (Hbmass) in both male and female children and adolescents and to evaluate the possible influences of altitude and training. Three-hundred and thirteen differentially trained boys and girls aged from 9 to 18 years and living at altitudes of 1000 and 2600 m above sea level entered the study. The stage of sexual maturation was determined according to the classification of Tanner. Testosterone was measured by ELISA. Hbmass was determined by CO-rebreathing. Haemoglobin concentration did not change during maturation in girls and was 11% higher during puberty in boys, while Hbmass was elevated by 33% in Tanner stage V compared to stage II in girls (498 ± 77 vs. 373 ± 88 g) and by 95% in boys (832 ± 143 vs. 428 ± 95 g). This difference can most likely be attributed to indirect testosterone influences through an increase in lean body mass (LBM) and to direct testosterone effects on erythropoiesis, which increase the Hbmass by â¼65 g per 1 ng/ml. Altitude and training statuses were not associated with testosterone, but with an increase in Hbmass (altitude by 1.1 g/kg LBM, training by 0.8 g/kg LBM). Changes in Hbmass are closely related to testosterone levels during male puberty. Further studies will show whether testosterone and Hbmass during childhood and adolescence can be used as diagnostic tools for endurance talents.
Asunto(s)
Eritropoyesis , Testosterona , Adolescente , Adulto , Composición Corporal , Niño , Estudios Transversales , Femenino , Humanos , Masculino , PubertadAsunto(s)
Elementos de Facilitación Genéticos , Hemoglobina H/genética , Globinas alfa/genética , Talasemia alfa/genética , Adulto , Alelos , Cromatina/genética , Cromatina/ultraestructura , Cromosomas Humanos Par 16/genética , Cromosomas Humanos Par 16/ultraestructura , Eritroblastos/patología , Eritropoyesis , Femenino , Eliminación de Gen , Regulación de la Expresión Génica , Genotipo , Hemoglobina E/genética , Hemoglobina H/análisis , Humanos , Masculino , Linaje , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Eliminación de Secuencia , Suriname/etnología , Globinas alfa/biosíntesis , Talasemia alfa/sangre , Globinas beta/genéticaRESUMEN
Introducción: Los defectos genéticos en la molécula de hemoglobina se dividen en aquellos que tienen una tasa reducida de producción de una o más cadenas de globina, las talasemias; y en los que se producen cambios estructurales que conducen a inestabilidad o transporte anormal de oxígeno. Objetivo: Explicar los diferentes mecanismos por los cuales ocurren las talasemias y otras alteraciones en la síntesis de las cadenas de globina, así como las características moleculares, fisiopatogénicas y los cambios hematológicos. Métodos: Se realizó una revisión de la literatura, en inglés y español, a través del sitio web PubMed y el motor de búsqueda Google académico de artículos publicados en los últimos 10 años. Se hizo un análisis y resumen de la bibliografía revisada. Análisis y síntesis de la información: Las talasemias son un grupo heterogéneo de defectos genéticos en la síntesis de hemoglobina, que causa una disminución en la tasa de producción de una o más cadenas de la molécula. De acuerdo a la cadena de globina que presenta el defecto se dividen en α-β-, δβ- o γδβ-talasemias. Conclusiones: Las talasemias y las hemoglobinopatías son las enfermedades hemolíticas hereditarias más comunes en muchas partes del mundo, caracterizadas por complejas interacciones entre anemia, eritropoyesis ineficaz y alteraciones del metabolismo del hierro(AU)
Introduction: Genetic disorders in the hemoglobin molecule are divided into those that have a reduced rate of production of one or more globin chains, thalassemias; and those in which structural changes occur that lead to instability or abnormal oxygen transport. Objective: To explain the different mechanisms by which thalassemias and other alterations in the synthesis of globin chains occur, as well as molecular, physiopathogenic and hematological changes. Methods: A review of the literature in English and Spanish was carried out through the PubMed website and the Google Scholar search engine, searching for articles published in the last ten years. The revised bibliography was analyzed and summarized. Information analysis and synthesis: Thalassemias make up a heterogeneous group of genetic defects in the synthesis of hemoglobin, which causes a decrease in the rate of production of one or more chains of the molecule. According to the globin chain that presents the defect, they are divided into α-β-, δβ- or γδβ-thalassemias. Conclusions: Thalassemias and hemoglobinopathies are the most common hereditary hemolytic diseases in many parts of the world. They are characterized by complex interactions between anemia, ineffective erythropoiesis, and alterations in iron metabolism(AU)
Asunto(s)
Humanos , Masculino , Femenino , Globinas , Eritropoyesis , Hemoglobinopatías/genética , Enfermedades Genéticas Congénitas/epidemiologíaRESUMEN
Este trabajo tiene como objetivo revisar las contribuciones de la biotecnología, en relación con el tratamiento, diagnóstico y la monitorización de la enfermedad renal crónica (ERC) y sus comorbilidades más frecuentes, especialmente la anemia. En relación con los tratamientos, enfocamos el desarrollo de productos biofarmacéuticos como los agentes estimulantes de la eritropoyesis (ESA), que fueron los primeros biofármacos utilizados para el tratamiento de la anemia asociada a la ERC; analizamos sus características y utilización actual después de varios años de experiencia clínica, así como también otras alternativas en desarrollo. Revisamos distintos tipos de bioterapias, la utilización de las células estromales mesenquimales de médula ósea (MSC) y tratamientos alternativos con modificaciones dietarias, que se basan en la asociación entre la microbiota intestinal de los pacientes renales crónicos y sus condiciones fisiopatológicas. Finalmente, en relación con el diagnóstico y monitorización, nos referimos al estudio y validación de biomarcadores diagnósticos, predictivos y terapéuticos que han permitido optimizar los resultados clínicos en este tipo de pacientes. (AU)
The aim of this work is to review the contributions of biotechnology, in relation to the treatment, diagnosis and monitoring of chronic kidney disease (CKD) and its most frequent comorbidities, especially anemia. Regarding the treatment, we focus on the development of biopharmaceutical products such as erythropoiesis stimulating agents (ESA), which were the first biopharmaceuticals used to treat anemia associated with chronic kidney disease (CKD). We analyzed their characteristics and their current use after several years of clinical experience, as well as other alternatives in development. We also review different types of biotherapies, the use of bone marrow mesenchymal stromal cells (MSC) and alternative treatments with dietary modifications, which are based on the association between the intestinal microbiota of chronic kidney patients and their pathophysiological conditions. Finally, in relation to diagnosis and monitoring, we refer to the study and validation of diagnostic, predictive and therapeutic biomarkers that have made clinical results possible to be optimized in this type of patient. (AU)
Asunto(s)
Humanos , Terapia Biológica/tendencias , Insuficiencia Renal Crónica/terapia , Calidad de Vida , Biotecnología , Biomarcadores , Eritropoyetina/deficiencia , Probióticos/uso terapéutico , Trasplante de Células Madre Mesenquimatosas/tendencias , Eritropoyesis/efectos de los fármacos , Insuficiencia Renal Crónica/diagnóstico , Insuficiencia Renal Crónica/dietoterapia , Insuficiencia Renal Crónica/rehabilitación , Prebióticos/clasificación , Inhibidores de Glicósido Hidrolasas/uso terapéutico , Microbioma Gastrointestinal , Hematínicos/administración & dosificación , Hematínicos/farmacología , Hematínicos/farmacocinética , Anemia/diagnóstico , Anemia/etiología , Anemia/tratamiento farmacológicoRESUMEN
ß-Thalassemia intermedia is a disorder characterized by ineffective erythropoiesis (IE), anemia, splenomegaly, and systemic iron overload. Novel approaches are being explored based on the modulation of pathways that reduce iron absorption (ie, using hepcidin activators like Tmprss6-antisense oligonucleotides [ASOs]) or increase erythropoiesis (by erythropoietin [EPO] administration or modulating the ability of transferrin receptor 2 [Tfr2] to control red blood cell [RBC] synthesis). Targeting Tmprss6 messenger RNA by Tmprss6-ASO was proven to be effective in improving IE and splenomegaly by inducing iron restriction. However, we postulated that combinatorial strategies might be superior to single therapies. Here, we combined Tmprss6-ASO with EPO administration or removal of a single Tfr2 allele in the bone marrow of animals affected by ß-thalassemia intermedia (Hbbth3/+). EPO administration alone or removal of a single Tfr2 allele increased hemoglobin levels and RBCs. However, EPO or Tfr2 single-allele deletion alone, respectively, exacerbated or did not improve splenomegaly in ß-thalassemic mice. To overcome this issue, we postulated that some level of iron restriction (by targeting Tmprss6) would improve splenomegaly while preserving the beneficial effects on RBC production mediated by EPO or Tfr2 deletion. While administration of Tmprss6-ASO alone improved the anemia, the combination of Tmprss6-ASO + EPO or Tmprss6-ASO + Tfr2 single-allele deletion produced significantly higher hemoglobin levels and reduced splenomegaly. In conclusion, our results clearly indicate that these combinatorial approaches are superior to single treatments in ameliorating IE and anemia in ß-thalassemia and could provide guidance to translate some of these approaches into viable therapies.
Asunto(s)
Eritropoyetina/administración & dosificación , Eritropoyetina/genética , Terapia Genética/métodos , Proteínas de la Membrana/antagonistas & inhibidores , Oligonucleótidos Antisentido/administración & dosificación , Talasemia beta/terapia , Animales , Células Cultivadas , Eritropoyesis/efectos de los fármacos , Eritropoyesis/genética , Regulación de la Expresión Génica/efectos de los fármacos , Hierro/metabolismo , Sobrecarga de Hierro/genética , Sobrecarga de Hierro/prevención & control , Masculino , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Oligonucleótidos Antisentido/farmacología , Receptores de Transferrina/genética , Serina Endopeptidasas/genética , Serina Endopeptidasas/metabolismo , Talasemia beta/metabolismoRESUMEN
During human pregnancy, iron requirements gradually increase, leading to higher amounts of erythropoietin (EPO) and reticulocytes, and changes in erythrocyte size and density. Women with pregestational obesity experience "obesity hypoferremia" during pregnancy, which alters iron homeostasis. In this study we aimed to describe the relationship between EPO and iron nutrition status during nonanemic pregnancy, and to explore whether obesity and inflammation influence erythropoiesis and red cell indices. We conducted a secondary analysis of a cohort followed throughout pregnancy. Participants were nonanemic women assigned to two study groups based on pregestational body mass index (pgBMI): adequate weight (AW, n = 53) or obesity (Ob, n = 40). All received a multivitamin supplement. At gestational ages (GA) 13, 21, 28 and 34, we measured hemoglobin and red cell indices with an ACT-5DIFF hematology counter, and reticulocyte percentage by manual cell counting. EPO, interleukin (IL-6) and markers of iron status, i.e., hepcidin, serum transferrin receptor (sTfr) and ferritin, were measured by ELISA. Bivariate correlations showed that EPO was positively associated with pgBMI, GA, sTfr and IL-6, but negatively associated with hepcidin, ferritin and hemoglobin, and unrelated to iron intake. Generalized linear models adjusted for confounding factors showed that EPO and erythrocyte concentrations were significantly higher in women in the Ob group, while mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH) and red cell distribution width (RDW) were lower; reticulocytes and mean corpuscular hemoglobin concentration (MCHC) were not different. Differences were not altered when controlling for inflammation (IL-6). These changes suggest that, in addition to altering iron metabolism, a larger maternal body size during pregnancy results in higher erythropoiesis without increasing hemoglobin, which is exhibited in the latter being distributed among more and smaller erythrocytes.
Asunto(s)
Tamaño Corporal , Índices de Eritrocitos , Eritropoyesis/fisiología , Fenómenos Fisiologicos Nutricionales Maternos , Obesidad Materna/sangre , Embarazo/sangre , Embarazo/fisiología , Adulto , Eritrocitos/patología , Eritropoyetina/sangre , Femenino , Humanos , Inflamación/sangre , Mediadores de Inflamación/sangre , Interleucina-6/sangre , Hierro/metabolismo , Adulto JovenRESUMEN
Erythropoiesis in the bone marrow and spleen depends on intricate interactions between the resident macrophages and erythroblasts. Our study focuses on identifying the role of nuclear factor erythroid 2-related factor 2 (Nrf2) during recovery from stress erythropoiesis. To that end, we induced stress erythropoiesis in Nrf2+/+ and Nrf2-null mice and evaluated macrophage subsets known to support erythropoiesis and erythroid cell populations. Our results confirm macrophage and erythroid hypercellularity after acute blood loss. Importantly, Nrf2 depletion results in a marked numerical reduction of F4/80+/CD169+/CD11b+ macrophages, which is more prominent under the induction of stress erythropoiesis. The observed macrophage deficiency is concomitant to a significantly impaired erythroid response to acute stress erythropoiesis in both murine bone marrow and murine spleen. Additionally, peripheral blood reticulocyte count as a response to acute blood loss is delayed in Nrf2-deficient mice compared with age-matched controls (11.0 ± 0.6% vs. 14.8 ± 0.6%, p ≤ 0.001). Interestingly, we observe macrophage hypercellularity in conjunction with erythroid hyperplasia in the bone marrow during stress erythropoiesis in Nrf2+/+ controls, with both impaired in Nrf2-/- mice. We further confirm the finding of macrophage hypercellularity in another model of erythroid hyperplasia, the transgenic sickle cell mouse, characterized by hemolytic anemia and chronic stress erythropoiesis. Our results revealed the role of Nrf2 in stress erythropoiesis in the bone marrow and that macrophage hypercellularity occurs concurrently with erythroid expansion during stress erythropoiesis. Macrophage hypercellularity is a previously underappreciated feature of stress erythropoiesis in sickle cell disease and recovery from blood loss.
Asunto(s)
Células de la Médula Ósea/metabolismo , Eritropoyesis , Macrófagos/metabolismo , Factor 2 Relacionado con NF-E2/deficiencia , Bazo/metabolismo , Estrés Fisiológico , Animales , Antígenos de Diferenciación/genética , Antígenos de Diferenciación/metabolismo , Células de la Médula Ósea/patología , Femenino , Macrófagos/patología , Masculino , Ratones , Ratones Noqueados , Factor 2 Relacionado con NF-E2/metabolismo , Bazo/patologíaRESUMEN
Serum soluble Fas (sFas) levels are associated with erythropoietin (Epo) hyporesponsiveness in patients with chronic kidney disease (CKD). Whether sFas could predict the need for erythropoiesis-stimulating agent (ESA) usage and its influence in erythropoiesis remain unclear. We evaluated the relation between sFas and ESA therapy in patients with CKD with anemia and its effect on erythropoiesis in vitro. First, we performed a retrospective cohort study with 77 anemic patients with nondialysis CKD. We performed in vitro experiments to investigate whether sFas could interfere with the behavior of hematopoietic stem cells (HSCs). HSCs were isolated from umbilical cord blood and incubated with recombinant sFas protein in a dose-dependent manner. Serum sFas positively correlated with Epo levels (r = 0.30, P = 0.001) but negatively with hemoglobin (r = -0.55, P < 0.001) and glomerular filtration rate (r = -0.58, P < 0.001) in patients with CKD at baseline. Elevated sFas serum levels (4,316 ± 897 vs. 2,776 ± 749, P < 0.001) with lower estimated glomerular filtration rate (26.2 ± 10.1 vs. 33.5 ± 14.3, P = 0.01) and reduced hemoglobin concentration (11.1 ± 0.9 vs. 12.5 ± 1.2, P < 0.001) were identified in patients who required ESA therapy compared with patients with non-ESA. Afterward, we detected that the sFas level was slight correlated with a necessity of ESA therapy in patients with nondialysis CKD and anemia. In vitro assays demonstrated that the erythroid progenitor cell frequency negatively correlated with sFas concentration (r = -0.72, P < 0.001). There was decreased erythroid colony formation in vitro when CD34+ HSCs were incubated with a higher concentration of sFas protein (1.56 ± 0.29, 4.33 ± 0.53, P < 0.001). Our findings suggest that sFas is a potential predictor for ESA therapy in patients with nondialysis CKD and that elevated sFas could affect erythropoiesis in vitro.
Asunto(s)
Anemia/sangre , Eritropoyesis , Células Madre Hematopoyéticas/metabolismo , Células Madre Multipotentes/metabolismo , Insuficiencia Renal Crónica/complicaciones , Receptor fas/sangre , Adulto , Anciano , Anemia/diagnóstico , Anemia/tratamiento farmacológico , Anemia/etiología , Biomarcadores/sangre , Brasil , Células Cultivadas , Toma de Decisiones Clínicas , Bases de Datos Factuales , Eritropoyesis/efectos de los fármacos , Eritropoyetina/sangre , Femenino , Hematínicos/uso terapéutico , Células Madre Hematopoyéticas/efectos de los fármacos , Hemoglobinas/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Células Madre Multipotentes/efectos de los fármacos , North Carolina , Selección de Paciente , Valor Predictivo de las Pruebas , Proteínas Recombinantes/farmacología , Insuficiencia Renal Crónica/sangre , Insuficiencia Renal Crónica/diagnóstico , Estudios RetrospectivosRESUMEN
In contrast to steady-state erythropoiesis, which generates new erythrocytes at a constant rate, stress erythropoiesis rapidly produces a large bolus of new erythrocytes in response to anemic stress. In this study, we illustrate that Yes-associated protein (Yap1) promotes the rapid expansion of a transit-amplifying population of stress erythroid progenitors in vivo and in vitro. Yap1-mutated erythroid progenitors failed to proliferate in the spleen after transplantation into lethally irradiated recipient mice. Additionally, loss of Yap1 impaired the growth of actively proliferating erythroid progenitors in vitro. This role in proliferation is supported by gene expression profiles showing that transiently amplifying stress erythroid progenitors express high levels of genes associated with Yap1 activity and genes induced by Yap1. Furthermore, Yap1 promotes the proliferation of stress erythroid progenitors in part by regulating the expression of key glutamine-metabolizing enzymes. Thus, Yap1 acts as an erythroid regulator that coordinates the metabolic status with the proliferation of erythroid progenitors to promote stress erythropoiesis.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/fisiología , Proteínas de Ciclo Celular/fisiología , Células Precursoras Eritroides/fisiología , Eritropoyesis/fisiología , Regeneración/fisiología , Proteínas Adaptadoras Transductoras de Señales/genética , Alelos , Animales , División Celular , Células Cultivadas , Inducción Enzimática , Células Precursoras Eritroides/citología , Eliminación de Gen , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Ratones , Ratones Endogámicos C57BL , ARN Mensajero/biosíntesis , Quimera por Radiación , Tolerancia a Radiación , Proteínas Recombinantes/metabolismo , Bazo/citología , Estrés Fisiológico/genética , Factores de Transcripción/genética , Proteínas Señalizadoras YAPRESUMEN
The lack of copper has been associated with anemia, myelodysplastic syndromes and leukemia as well as with a loss in complex IV activity and an enlarged mitochondrial morphology. Mitochondria play a key role during the differentiation of hematopoietic stem cells by regulating the passage from a glycolytic to oxidative metabolism. The former is associated with cell proliferation and the latter with cell differentiation. Oxidative metabolism, which occurs inside mitochondria, is sustained by the respiratory chain, where complex IV is copper-dependent. We have hypothesized that a copper deficiency induces a mitochondrial metabolic reprogramming, favoring cell expansion over cell differentiation in erythropoiesis. Erythroid progression analysis of the bone marrow of mice fed with a copper deficient diet and of the in vitro erythropoiesis of human CD34+ cells treated with a bathocuproine - a copper chelator - showed a major expansion of progenitor cells and a decreased differentiation. Under copper deficiency, mitochondria switched to a higher membrane potential, lower oxygen consumption rate and lower ROS levels as compared with control cells. In addition, mitochondrial biomass was increased and an up-regulation of the mitochondrial fusion protein mitofusin 2 was observed. Most copper-deficient phenotypes were mimicked by the pharmacological inhibition of complex IV with azide. We concluded that copper deficiency induced a mitochondrial metabolic reprogramming, making hematopoietic stem cells favor progenitor cell expansion over cell differentiation.
Asunto(s)
Proliferación Celular/fisiología , Leucocitos Mononucleares/metabolismo , Animales , Western Blotting , Proliferación Celular/genética , Células Cultivadas , Cobre/metabolismo , Eritropoyesis/genética , Eritropoyesis/fisiología , Citometría de Flujo , Humanos , Ratones , Ratones Endogámicos BALB C , Microscopía Confocal , Mitocondrias/metabolismo , Proteínas Mitocondriales/metabolismoRESUMEN
ß-Thalassemia (BT) is an inherited genetic disorder that is characterized by ineffective erythropoiesis (IE), leading to anemia and abnormal iron metabolism. IE is an abnormal expansion of the number of erythroid progenitor cells with unproductive synthesis of enucleated erythrocytes, leading to anemia and hypoxia. Anemic patients affected by BT suffer from iron overload, even in the absence of chronic blood transfusion, suggesting the presence of ≥1 erythroid factor with the ability to modulate iron metabolism and dietary iron absorption. Recent studies suggest that decreased erythroid cell differentiation and survival also contribute to IE, aggravating the anemia in BT. Furthermore, hypoxia can also affect and increase iron absorption. Understanding the relationship between iron metabolism and IE could provide important insights into the BT condition and help to develop novel treatments. In fact, genetic or pharmacological manipulations of iron metabolism or erythroid cell differentiation and survival have been shown to improve IE, iron overload, and anemia in animal models of BT. Based on those findings, new therapeutic approaches and drugs have been proposed; clinical trials are underway that have the potential to improve erythrocyte production, as well as to reduce the iron overload and organ toxicity in BT and in other disorders characterized by IE.
Asunto(s)
Eritropoyesis , Trastornos del Metabolismo del Hierro/etiología , Trastornos del Metabolismo del Hierro/patología , Hierro/metabolismo , Talasemia beta/complicaciones , Animales , Humanos , Talasemia beta/patologíaRESUMEN
Anemia is an inevitable complication of hemodialysis, and the primary cause is erythropoietin deficiency. After diagnosis, treatment begins with an erythropoiesis-stimulating agent (ESA). However, some patients remain anemic even after receiving this medication. This study aimed to investigate the factors associated with resistance to recombinant human erythropoietin therapy with epoetin alfa (αEPO). We performed a prospective, longitudinal study of hemodialysis patients receiving treatment with αEPO at our reference hospital from July 2015 to June 2016. Clinical data was collected, and the response to αEPO treatment was evaluated using the erythropoietin resistance index (ERI). The ERI was defined as the weekly weight-adjusted αEPO dose (U/kg per week)/hemoglobin level (g/dL). A longitudinal linear regression model was fitted with random effects to verify the relationships between clinical and laboratory data and ERI. We enrolled 99 patients (average age, 45.7 (±17.6) years; male, 51.5%; 86.8% with hypertension). The ERI showed a significant positive association with serum ferritin and C-reactive protein, percentage interdialytic weight gain, and continuous usage of angiotensin receptor blocker (ARB) hypertension medication. The ERI was negatively associated with serum iron and albumin, age, urea reduction ratio, and body mass index. Our findings indicate that resistance to αEPO was related to a low serum iron reserve, an inflammatory state, poor nutritional status, and continuous usage of ARBs.
Asunto(s)
Anemia/tratamiento farmacológico , Anemia/etiología , Resistencia a Medicamentos/efectos de los fármacos , Epoetina alfa/uso terapéutico , Hematínicos/uso terapéutico , Diálisis Renal/efectos adversos , Insuficiencia Renal Crónica/terapia , Adulto , Índice de Masa Corporal , Eritropoyesis/efectos de los fármacos , Eritropoyetina/deficiencia , Femenino , Hemoglobinas/análisis , Humanos , Hierro/sangre , Modelos Lineales , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Valores de Referencia , Insuficiencia Renal Crónica/complicaciones , Factores de Riesgo , Factores de Tiempo , Resultado del TratamientoRESUMEN
Immunosuppression is a well-established risk factor for Visceral Leishmaniasis. Post-immunosuppression leishmaniasis is characterized by an increase of parasite burden, hematopoietic disorders and unusual clinical manifestations. Although there are many reports on bone marrow findings in VL, less is known about the relationship between parasite dynamics in this organ and the function of either hematopoietic stem cells and progenitor cells themselves. In the present study, we tackle these issues using a new approach of infecting human stem cells derived from bone marrow with L. infantum. Using this strategy, we show that human hematopoietic stem cells (hHSC) are able to phagocytize L. infantum promastigotes and release modulatory and pro-inflammatory cytokines, mainly TNF-α. Our results demonstrated that L. infantum infection in vitro enhances hematopoiesis, favoring the development of erythrocitic lineage through a mechanism yet unknown. Moreover, we found that L. infantum infection alters the phenotypic profile of the hematopoietic progeny; modifying the surface markers expression of differentiated cells. Thus, our study represents a rare opportunity to monitor the in vitro differentiation of human stem cells experimentally infected by L. infantum to better understand the consequences of the infection on phenotypic and functional profile of the cell progeny.
Asunto(s)
Diferenciación Celular/inmunología , Eritropoyesis/inmunología , Células Madre Hematopoyéticas/inmunología , Leishmania infantum/inmunología , Fagocitosis/inmunología , Adulto , Anciano , Células de la Médula Ósea/inmunología , Células de la Médula Ósea/metabolismo , Células de la Médula Ósea/parasitología , Citocinas/inmunología , Citocinas/metabolismo , Femenino , Células Madre Hematopoyéticas/metabolismo , Células Madre Hematopoyéticas/parasitología , Interacciones Huésped-Parásitos/inmunología , Humanos , Leishmania infantum/fisiología , Masculino , Persona de Mediana Edad , Factor de Necrosis Tumoral alfa/inmunología , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Anemia is an inevitable complication of hemodialysis, and the primary cause is erythropoietin deficiency. After diagnosis, treatment begins with an erythropoiesis-stimulating agent (ESA). However, some patients remain anemic even after receiving this medication. This study aimed to investigate the factors associated with resistance to recombinant human erythropoietin therapy with epoetin alfa (αEPO). We performed a prospective, longitudinal study of hemodialysis patients receiving treatment with αEPO at our reference hospital from July 2015 to June 2016. Clinical data was collected, and the response to αEPO treatment was evaluated using the erythropoietin resistance index (ERI). The ERI was defined as the weekly weight-adjusted αEPO dose (U/kg per week)/hemoglobin level (g/dL). A longitudinal linear regression model was fitted with random effects to verify the relationships between clinical and laboratory data and ERI. We enrolled 99 patients (average age, 45.7 (±17.6) years; male, 51.5%; 86.8% with hypertension). The ERI showed a significant positive association with serum ferritin and C-reactive protein, percentage interdialytic weight gain, and continuous usage of angiotensin receptor blocker (ARB) hypertension medication. The ERI was negatively associated with serum iron and albumin, age, urea reduction ratio, and body mass index. Our findings indicate that resistance to αEPO was related to a low serum iron reserve, an inflammatory state, poor nutritional status, and continuous usage of ARBs.