Articles de revues : « Sickle cells diseases »

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Ashwi, Shaima, Ahmad Alobaisy, Nawal Herzallah, Fatema Alwaheed, Ibtihal Hadi, Duaa Alabbas, Faisal Al-Rasheed, Nawaf Alshuraym et Esra Alzein. « Atopic dermatitis in sickle cell children ». International Journal Of Community Medicine And Public Health 5, n^o 3 (24 février 2018) : 842. http://dx.doi.org/10.18203/2394-6040.ijcmph20180420.

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Sickle cell disease is an autosomal recessive disease characterized by recurrent vaso-occlusive events. Despite the genetic basis of its pathophysiology, recent researchers stated that it is an inflammatory immune-mediated disease where inflammation plays a crucial role in the initiation of adherence between sickle cells and vascular endothelial cells. Allergic, as well as infectious, inflammation is proposed to contribute to the initiation of vaso-occlusive events. Although several researchers reported an association between sickle cell disease and atopic conditions such as bronchial asthma and allergic rhino-conjunctivitis, few cases have reported an association between sickle cell disease and atopic dermatitis. Atopy was reported to be considerably linked to sickle cell disease for several reasons. Firstly, patients with sickle cell disease have higher IgE levels than the general population. Secondly, the mechanism of activation of molecular adhesion between endothelial and blood cells are similar between both sickle cell disease and atopic disease. Thirdly, the cytokines produced from platelet activation are the same cytokines that stimulate allergic inflammation in atopic diseases and promote adherence of sickle cells and endothelium in sickle cell disease. Lastly, sickle cell disease was reported to be associated with other atopic diseases.

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Akhter, Mohammad S., Hassan A. Hamali, Hina Rashid, Gasim Dobie, Aymen M. Madkhali, Abdullah A. Mobarki, Johannes Oldenburg et Arijit Biswas. « Mitochondria : Emerging Consequential in Sickle Cell Disease ». Journal of Clinical Medicine 12, n^o 3 (18 janvier 2023) : 765. http://dx.doi.org/10.3390/jcm12030765.

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Advanced mitochondrial multi-omics indicate a multi-facet involvement of mitochondria in the physiology of the cell, changing the perception of mitochondria from being just the energy-generating organelles to organelles that highly influence cell structure, function, signaling, and cell fate. This sets mitochondrial dysfunction in the centerstage of numerous acquired and genetic diseases. Sickle cell disease is also being increasingly associated with mitochondrial anomalies and the pathophysiology of sickle cell disease finds mitochondria at crucial intersections in the pathological cascade. Altered mitophagy, increased ROS, and mitochondrial DNA all contribute to the condition and its severity. Such mitochondrial aberrations lead to consequent mitochondrial retention in red blood cells in sickle cell diseases, increased oxidation in the cellular environment, inflammation, worsened vaso-occlusive crisis, etc. There are increasing studies indicating mitochondrial significance in sickle cell disease, consequently providing an opportunity to target it for improving the outcomes of treatment. Identification of the impaired mitochondrial attributes in sickle cell disease and their modulation by therapeutic interventions can impart a better management of the disease. This review aims to describe the mitochondria in the perspective of sicke cell disease so as to provide the reader an overview of the emerging mitochondrial stance in sickle cell disease.

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Amorim, Maria do Socorro do N., Jerias A. Batista, Francisco Maia Junior, Adriana Fontes, Ralph Santos-Oliveira et Luciana M. Rebelo Alencar. « New Insights into Hemolytic Anemias : Ultrastructural and Nanomechanical Investigation of Red Blood Cells Showed Early Morphological Changes ». Journal of Biomedical Nanotechnology 18, n^o 2 (1 février 2022) : 405–21. http://dx.doi.org/10.1166/jbn.2022.3267.

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Several diseases are characterized by changes in the mechanical properties of erythrocytes. Hemolytic anemias are an example of these diseases. Among the hemolytic anemias, Sickle Cell Disease and Thalassemia are the most common, characterized by alterations in the structure of their hemoglobin. Sickle cell disease has a pathological origin in synthesizing abnormal hemoglobin, HbS. In contrast, thalassemia results in extinction or decreased synthesis of α and β hemoglobin chains. This work presents a detailed study of biophysical and ultrastructural early erythrocytes membrane alterations at the nanoscale using Atomic Force Microscopy (AFM). Cells from individuals with sickle cell anemia and thalassemia mutations were studied. The analysis methodology in the AFM was given by blood smear and exposure of the inner membrane for ghost analysis. A robust statistic was used with 65,536 force curves for each map, ten cells of each type, with three individuals for each sample group. The results showed significant differences in cell rigidity, adhesion, volume, and roughness at early morphological alterations, bringing new perspectives for understanding pathogenesis. The sickle cell trait (HbAS) results stand out. Significant alterations were observed in the membrane properties, bringing new perspectives for the knowledge of this mutation. This work presents ultrastructural and biomechanical signatures of sickle cell anemia and thalassemia genotypes, which may help determine a more accurate biophysical description and clinical prognosis for these diseases.

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Lim, Teck Chwee. « Single Cell Mechanics and its connections to Human Diseases ». Asia-Pacific Biotech News 09, n^o 14 (30 juillet 2005) : 674–75. http://dx.doi.org/10.1142/s0219030305001916.

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The article is about single cell mechanics and its connection to human diseases. It touches on the biomechanics used to perform quantitative study in the physical properties of cells with the progression of certain diseases such as malaria, sickle cell anemia and cancer.

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Parrish, James M., Paul A. Page, David Cohen, Mark R. Nyreen, Charles P. Kingsley, Tara Chronister, Berry F. Shesol et Richard Drew. « Prebypass Pheresis and Red Blood Cell Exchange in a Patient with Homozygous SS Sickle Cell Disease Undergoing Cardiopulmonary Bypass : A Case Report ». Journal of ExtraCorporeal Technology 26, n^o 3 (septembre 1994) : 143–51. http://dx.doi.org/10.1051/ject/1994263143.

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Sickle cell disease was first described by Herrick in 1910. This disease involves an abnormality of the hemoglobin molecule which, under certain conditions, causes the red cell to take on a sickle shape. This abnormal shape and hemoglobin prevent the red cell from performing the normal respiratory functions and interfere with the normal flow through the circulatory system. Individuals demonstrate either a homozygous (dominant) SS or a heterozygous Ss state. Clinical symptoms for patients with SS disease are most often characterized by recurrent painful crises, sequestration of sickled cells, chronic hemolytic anemia, systemic diseases, vasoocclusive crises, permanent organ damage and recurrent infection. These patients usually require exchange transfusions due to the concern that the stress of surgery will precipitate a sickling crisis. Exchange transfusions require large amounts of homologous red blood cells (RBCs) to lower the percentage of the homozygous SS hemoglobin. The use of autologous pheresis in the peri operative period reduces the amount of homologous RBCs required and lowers the patient's exposure to homologous blood and its associated risks. This paper discusses the disease, the planning and the techniques for prebypass pheresis and red cell exchange in a patient with homozygous SS hemoglobin sickle cell disease undergoing cardiopulmonary bypass.

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Laure Kpoumie, Carolle. « Gene Therapy : The New Weapon Against Diseases Until There Difficult To Overcome : Some Current Facts Of Gene Therapy And Cases Of Sickle Cell Anaemia ». Journal of Clinical Research and Reports 4, n^o 3 (8 juin 2020) : 01–07. http://dx.doi.org/10.31579/2690-1919/075.

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Sickle cell anaemia is an inherited genetic disease that affects the hemoglobin chains of red blood cell hemoglobin, carrying oxygen less well through the body. It is a rare disease, however, it is the most widespread genetic disease in the world and especially widespread in sub-Saharan Africa. It causes anemia, painful seizures that affect several organs, it is also called sickle cell anemia, this disease results in a deformation of red blood cells in the form of sickle or a crescent moon, which prevents normal circulation in the blood vessels. This will cause blood flow to be blocked. It is a disease that is geographically concentrated in certain areas such as Africa, India, Brazil, the Mediterranean Basin, but it is currently found everywhere because of mass migration and has been considered since 2008 by United Nations as a public health priority. Sickle cell disease affects black people and accounts for 50% of deaths in childhood.

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Darghouth, Dhouha, Bérengère Koehl, Geoffrey Madalinski, Jean-François Heilier, Petra Bovee, Ying Xu, Marie-Françoise Olivier et al. « Pathophysiology of sickle cell disease is mirrored by the red blood cell metabolome ». Blood 117, n^o 6 (10 février 2011) : e57-e66. http://dx.doi.org/10.1182/blood-2010-07-299636.

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Abstract Emerging metabolomic tools can now be used to establish metabolic signatures of specialized circulating hematopoietic cells in physiologic or pathologic conditions and in human hematologic diseases. To determine metabolomes of normal and sickle cell erythrocytes, we used an extraction method of erythrocytes metabolites coupled with a liquid chromatography-mass spectrometry–based metabolite profiling method. Comparison of these 2 metabolomes identified major changes in metabolites produced by (1) endogenous glycolysis characterized by accumulation of many glycolytic intermediates; (2) endogenous glutathione and ascorbate metabolisms characterized by accumulation of ascorbate metabolism intermediates, such as diketogulonic acid and decreased levels of both glutathione and glutathione disulfide; (3) membrane turnover, such as carnitine, or membrane transport characteristics, such as amino acids; and (4) exogenous arginine and NO metabolisms, such as spermine, spermidine, or citrulline. Finally, metabolomic analysis of young and old normal red blood cells indicates metabolites whose levels are directly related to sickle cell disease. These results show the relevance of metabolic profiling for the follow-up of sickle cell patients or other red blood cell diseases and pinpoint the importance of metabolomics to further depict the pathophysiology of human hematologic diseases.

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Simões, Belinda Pinto, Fabiano Pieroni, Thalita Costa, George Navarro Barros, Guilherme Darrigo Jr., Carlos Settani Grecco, Juliana Elias Bernardes et al. « Allogenic bone narrow transplantation in sickle-cell diseases. » Revista da Associação Médica Brasileira 62, suppl 1 (octobre 2016) : 16–22. http://dx.doi.org/10.1590/1806-9282.62.suppl1.16.

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SUMMARY Sickle-cell diseases are the most common inherited hemoglobinopathies worldwide. Improvement in survival has been seen in the last decades with the introduction of careful screening and prevention of complications and the introduction of hydroxyurea. Stem-cell transplantation is currently the only curative option for these patients and has been indicated for patients with neurological events, repeated vaso-occlusive crisis, any organ damage or presence of red blood cell antibodies. Related bone-marrow or cord-blood transplant has shown an overall survival of more than 90% with a disease-free survival of 90% in 1,000 patients transplanted in the last decades. The use of unrelated donors unfortunately has not shown the same good results, but better typing methods and improved support may improve the outcome with this source of stem cells in the future. In Brazil, only recently stem cell transplant from related donors has been included in the procedures performed in the public health system. The use of related bone marrow or cord blood and a myeloablative conditioning regimen are considered standard of care for patients with sickle-cell diseases. Transplants with non-myeloablative regimens, unrelated donors or haploidentical donors should be performed only in controlled clinical trials.

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Pryzhkova, Marina, Xuan Yuan, Abhai Tripathi, David Sullivan et Elias Zambidis. « Efficient Erythroid Differentiation of a PGD-Derived Human Pluripotent Stem Cell Line Affected with Sickle Cell Hemoglobinopathy ». Blood 112, n^o 11 (16 novembre 2008) : 539. http://dx.doi.org/10.1182/blood.v112.11.539.539.

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Abstract The technology of preimplantation genetic diagnosis (PGD) screens IVF-derived cleavage-stage embryos or oocytes from parents with inherited disorders, and is routinely used to avoid births with severe genetic disorders. More than one hundred testable genetic conditions, including severe hematologic diseases such as beta thalassemia, sickle cell anemia, and Fanconi anemia can be PCR-screened from either a micro-manipulated blastomere, or a pre-fertilization ovarian polar body. Derivation of human embryonic stem cell (hESC) lines from diseased IVF blastocysts has recently been reported, and these PGD-hESC are untested yet potentially valuable tools for investigating cellular and molecular events of human embryogenesis in diseased states. For example, a great deal of interest has recently been generated in treating hematologic diseases with genetically-corrected hematopoietic stem cells (HSC) derived from patient-specific pluripotent stem cells. Generation of hematopoietic progenitors from PGD-hESC affected with genetic syndromes may thus provide novel opportunities for testing cell-based and gene therapeutic strategies. An important candidate for such cell-based therapy includes sickle cell disease (SSD) hemoglobinopathy, a classic inherited single gene disorder resulting from the substitution of glutamic acid by valine at position 6 of the beta chain of hemoglobin. Human pluripotent stem cells derived from PGD-selected blastocysts or induced pluripotency (iPS; e.g., using patient’s somatic cells), will serve as critical reagents for testing such therapeutic strategies. In these studies, we report the characterization and erythropoietic differentiation of a novel PGD-hESC line affected with SSD hemoglobinopathy. The sickle point mutation was confirmed in this PGD-hESC line with direct genomic sequencing of the beta globin locus. This hESC line possesses typical pluripotency characteristics and forms multilineage teratomas in vivo. SSD-hESC can be efficiently differentiated to the hematopoietic lineage under serum-free conditions, and gave rise to robust primitive and definitive erythropoieses. The expression of embryonic, fetal and adult globin genes in SSD PGD-hESC derived erythroid cells was confirmed by qRT-PCR, intracytoplasmic FACS, and in situ immunostaining of PGD-hESC teratoma sections. Moreover, we defined culture conditions for massive, long-term liquid culture expansion of sickle affected erythroid progenitors that remained in an undifferentiated erythroblastic phenotype for at least two months. These sickle erythroblasts were continuously maintained as a primary cell line that could be frozen and thawed without loss of viability. In vitro-expanded sickle erythroblasts expressed CD71+CD36+ and CD71+CD235a+ phenotypes, and underwent developmentally appropriate embryonic, fetal, and adult hemoglobin switching over a period of several months. Moreover, hESC-derived erythroblasts were readily infected with Plasmodium falciparum malaria parasites, thus demonstrating their potential utility in studying the effects of this important pathogen in normal and diseased erythropoiesis. These data demonstrate the utility of using patient-specific, hemoglobinopathic hESC for generating significant numbers of erythroid progenitors for molecular, developmental, gene therapeutic, pharmacologic, and microbiological studies. We are currently conducting a comparative erythropoietic differentiation study using SSD PGD-hESC vs. SSD iPS that were generated from somatic fibroblasts using defined pluripotency factors.

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Williams, David A., et Erica Esrick. « Investigational curative gene therapy approaches to sickle cell disease ». Blood Advances 5, n^o 23 (14 décembre 2021) : 5452. http://dx.doi.org/10.1182/bloodadvances.2021005567.

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Abstract Sickle cell disease (SCD) is an inherited blood condition resulting from abnormal hemoglobin production. It is one of the most common genetic diseases in the world. The clinical manifestations are variable and range from recurrent acute and debilitating painful crises to life-threatening pulmonary, cardiovascular, renal, and neurologic complications. The only curative treatment of SCD at this time is bone marrow transplantation (also called hematopoietic stem cell transplantation) using healthy blood stem cells from an unaffected brother or sister or from an unrelated donor if one can be identified who is a match in tissue typing. Unfortunately, only a minority of patients with sickle cell has such a donor available. The use of autologous hematopoietic stem cells and alternative types of genetic modifications is currently under study in clinical research trials for this disease. The approaches include the use of viral vectors to express globin genes that are modified to prevent sickle hemoglobin polymerization or to express interfering RNAs to “flip the switch” in adult red cells from adult β-sickle hemoglobin to fetal hemoglobin using a physiologic switch, and several gene editing approaches with the goal of inducing fetal hemoglobin or correcting/modifying the actual sickle mutation. In this audio review, we will discuss these different approaches and review the current progress of curative therapy for SCD using gene therapy.

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Behera, Arabinda, Gaurav Kumar et Anirban Sain. « Confined filaments in soft vesicles – the case of sickle red blood cells ». Soft Matter 16, n^o 2 (2020) : 421–27. http://dx.doi.org/10.1039/c9sm01872g.

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Claudino, Mário Angelo, et Kleber Yotsumoto Fertrin. « Sickling Cells, Cyclic Nucleotides, and Protein Kinases : The Pathophysiology of Urogenital Disorders in Sickle Cell Anemia ». Anemia 2012 (2012) : 1–13. http://dx.doi.org/10.1155/2012/723520.

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Sickle cell anemia is one of the best studied inherited diseases, and despite being caused by a single point mutation in theHBBgene, multiple pleiotropic effects of the abnormal hemoglobin S production range from vaso-occlusive crisis, stroke, and pulmonary hypertension to osteonecrosis and leg ulcers. Urogenital function is not spared, and although priapism is most frequently remembered, other related clinical manifestations have been described, such as nocturia, enuresis, increased frequence of lower urinary tract infections, urinary incontinence, hypogonadism, and testicular infarction. Studies on sickle cell vaso-occlusion and priapism using bothin vitroandin vivomodels have shed light on the pathogenesis of some of these events. The authors review what is known about the deleterious effects of sickling on the genitourinary tract and how the role of cyclic nucleotides signaling and protein kinases may help understand the pathophysiology underlying these manifestations and develop novel therapies in the setting of urogenital disorders in sickle cell disease.

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Orrico, Florencia, Sandrine Laurance, Ana C. Lopez, Sophie D. Lefevre, Leonor Thomson, Matias N. Möller et Mariano A. Ostuni. « Oxidative Stress in Healthy and Pathological Red Blood Cells ». Biomolecules 13, n^o 8 (18 août 2023) : 1262. http://dx.doi.org/10.3390/biom13081262.

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Red cell diseases encompass a group of inherited or acquired erythrocyte disorders that affect the structure, function, or production of red blood cells (RBCs). These disorders can lead to various clinical manifestations, including anemia, hemolysis, inflammation, and impaired oxygen-carrying capacity. Oxidative stress, characterized by an imbalance between the production of reactive oxygen species (ROS) and the antioxidant defense mechanisms, plays a significant role in the pathophysiology of red cell diseases. In this review, we discuss the most relevant oxidant species involved in RBC damage, the enzymatic and low molecular weight antioxidant systems that protect RBCs against oxidative injury, and finally, the role of oxidative stress in different red cell diseases, including sickle cell disease, glucose 6-phosphate dehydrogenase deficiency, and pyruvate kinase deficiency, highlighting the underlying mechanisms leading to pathological RBC phenotypes.

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Rehani, Teena, Kristin Mathson, John D. Belcher, Gregory M. Vercellotti et Arne Slungaard. « Heme Potently Stimulates Tissue Factor Expression By Peripheral Blood Monocytes : A Novel Mechanism For Thrombosis In Intravascular Hemolytic Diseases ». Blood 122, n^o 21 (15 novembre 2013) : 2215. http://dx.doi.org/10.1182/blood.v122.21.2215.2215.

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Abstract Intravascular hemolytic diseases such as sickle cell anemia as well as diseases such as sepsis/DIC in which intravascular hemolysis occurs are frequently complicated by micro- and macrovascular thrombosis but mechanisms underlying this association are unclear. Plasma heme levels in sickle cell anemia are typically 5-30 µM. LPS is a prototypic and potent agonist for peripheral blood monocyte tissue factor expression and by this mechanism contributes to thrombosis in sepsis. Because heme, like LPS, signals by binding to and activating TLR4, we hypothesized that heme would also stimulate tissue factor expression in monocytes and so promote thrombosis in sickle cell anemia. We isolated human peripheral blood mononuclear cells (PBMC) and monocytes, incubated them 4 hours in the presence or absence of 10 µM hemin or 10 ng/ml LPS, made whole cell lysates by freeze-thawing and sonication and measured tissue factor activity using a one-stage clotting assay employing recalcified citrated human plasma. The assay was standardized with recombinant human tissue factor and the tissue factor dependence of the assay was confirmed using the neutralizing anti-human tissue factor antibody ATF. Hemin stimulated PBMC TF activity ca. 40-fold (range 6- to 296-fold) from 53 to 1885 pg/ml/million cells, an extent comparable to that of LPS (1939 pg/ml/million cells). In isolated monocytes heme increased TF activity ca. 70-fold (range 25-115-fold) to 9800 pg/ml/million cells, again comparable to LPS (8500 pg/ml/million cells.) Heme stimulation of monocyte TF expression did not reflect endotoxin contamination of our hemin preparation because it was 1) reproduced with a preparation of hemin made for infusion into patients with intermittent porphyria that had no detectable endotoxin; 2) unaffected by addition of 1 µg polymyxin B, which abrogated LPS stimulation; 3) blocked by 15 µM hemopexin, a high affinity heme-binding protein. qRT-PCR of TF expression in monocytes shows a 140-350-fold increase in TF mRNA levels over baseline between 2 and 4 hours after exposure to heme. Examining pathways for heme signaling, we demonstrate that heme stimulation of TF expression in monocytes is impaired > 90% by inhibitors of TLR4 (TAK242), NADPH oxidase (diphenylene iodonium), PKC (5 µM calphostin) and ERK ½ (10 µM U-0126), impaired 75% by the p50 NF-kB inhibitor 10 µg/ml andrographolide and unaffected by 100 nM wortmannin, an AKT/PI3K pathway inhibitor. We conclude that heme, at concentrations found in intravascular hemolytic diseases such as sickle cell anemia, is a highly potent stimulant of blood monocyte TF transcriptional expression dependent upon signaling through TLR4, PKC, NADPH oxidase, ERK ½ and NF-kB. By this direct mechanism heme may promote thrombosis and contribute to the pathogenesis of sickle cell anemia and other diseases characterized by intravascular hemolysis, including sepsis/DIC. Disclosures: No relevant conflicts of interest to declare.

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Abdullah, Esraa Hasan, Rawand Polus Shamoon et Nawsherwan Sadiq Mohammad. « Cholelithiasis in Patients with Sickle Cell Disease and Sickle/Beta-Thalassemia in Akre City, Kurdistan Region of Iraq ». Advanced medical journal 9, n^o 1 (10 mars 2024) : 19–27. http://dx.doi.org/10.56056/amj.2024.233.

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Background and objectives: Sickle cell disease and sickle β-thalassemia are hemolytic diseases characterized by chronic destruction of the abnormal red cells with consequent hyperbilirubinemia. The present study aimed to determine the association of gallstone with Sickle cell disease and sickle β-thal patients compared to the control healthy group and to determine gallstone's association with several demographic and laboratory parameters among the patients themselves. Methods: Patients visiting the Akre thalassemia center for routine checks have been recruited for this study (patients=73; control=36). Blood samples were collected for biochemical and haematological analyses. All participants were subjected to abdominal ultrasonography for confirmation of gallstones. These parameters were compared with patients' subtype traits. Additional information regarding blood transfusion, hospital admission, and the use of chelating agents was also allocated. Results: The prevalence of gallstone was significantly higher in patients (12%) than in the control (3%) group (P<0.05), with similar prevalence in both trait; homozygous haemoglobin S (14%) and compound heterozygous of hemoglobin S and β-thalassemia (11%), together with significant differences in the biochemical and haematological parameters. The haemoglobin concentration was significantly (P<0.05) reduced in patients (8.5±0.86) versus control (12±1.6). Reticulocytes, lactate dehydrogenase enzyme, and bilirubin were significantly (P<0.05) elevated in patients compared to the control. No differences existed between control versus patients regarding hospital admission, blood transfusion, and the use of medication including chelating agent or hydroxyurea. Conclusion: Sickle-diseased and sickle beta-thalassemia patients have a higher risk of developing gallstones than the general population alongside interruption of metabolic and biochemical parameters with co-association with sub-traits of type of haemoglobin.

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Khan, Mohammad Monirujjaman, Tahia Tazin et Tabia Hossain. « An Automatic Blood Cell Separation Machine with Disease Detection System : Perspective in Bangladesh ». Proceedings 67, n^o 1 (9 novembre 2020) : 9. http://dx.doi.org/10.3390/asec2020-07547.

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Blood is a liquid that transports oxygen and supplements to cells and diverts carbon dioxide and other byproducts. Red blood cells principally carry oxygen and gather carbon dioxide using hemoglobin. Hereditary disease of the blood comprises hemoglobinopathies, which is a significant common health issue in Bangladesh. Sickle cell disorder alludes to the gathering of hereditary issues described by the presence of sickle hemoglobin, sickliness, schistocytes, intense and ongoing tissue injury and blockage of the bloodstream by anomalously formed red cells. Schistocytes are additionally a critical marker of a perilous condition aﬀecting a human patient. In the cutting-edge setting, only the most modern computerized cell counters ﬂag their administrators if a schistocyte is identified and few of them can provide a schistocyte tally. By analyzing these issues, in this paper, we propose to create an automatic system that will allow blood cells to be separated very quickly, and with this, blood diseases can be also identified.

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Park, So Hyun, Ciaran M. Lee, Yankai Zhang, Alicia Chang, Vivien A. Sheehan et Gang Bao. « Engineered Human Umbilical Cord Derived Erythroid Progenitor Cells (HUDEP2) with Sickle or β-Thalassemia Mutation : An in-Vitro System for Testing Pharmacological Induction of Fetal Hemoglobin ». Blood 132, Supplement 1 (29 novembre 2018) : 3478. http://dx.doi.org/10.1182/blood-2018-99-114241.

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Abstract Introduction: Sickle cell disease (SCD) and β-thalassemia are inherited blood disorders caused by mutations in the β-globin gene (HBB). Elucidation of the multiple pathophysiologic mechanisms in SCD and β-thalassemia has resulted in an increasing efforts to identify new treatment modalities to ameliorate the consequences of the disease. However, no consistent in vitro system exists for studies of pharmacological therapies for the diseases. Human umbilical cord-derived erythroid progenitor cells (HUDEP2) are an immortalized CD34+ hematopoietic stem cell-derived erythroid precursor cell line that can differentiate into red blood cells. Here, we engineered sickle HUDEP2 and β-thalassemia HUDEP2 clonal lines through CRISPR/Cas9-mediated editing of the human HBB. We sought to establish if these engineered cell lines exhibit disease phenotypes, and if upon in vitro erythroid differentiation they produce fetal hemoglobin (HbF) in response to hydroxyurea, the only FDA-approved drug for HbF induction. Our goal is to create an in vitro system to test new HbF inducers for treating SCD or β-thalassemia. Materials and Methods: We delivered Hi-Fidelity Streptococcus pyogenes (Sp) Cas9 protein and CRISPR guide RNA as a ribonucleoprotein complex in conjunction with a single-stranded DNA donor (ssODN) template to introduce the sickle or K17X (A<T) or codon 6 [-G] β-thalassemia mutation into the HBB locus of HUDEP2 cells. Edited HUDEP2 cells were single-cell sorted into multiple 96-well plates and expanded. The genotype of the clones was determined using a probe-based droplet digital PCR assay and confirmed through Sanger sequencing. Native polyacrylamide gel electrophoresis and high-performance liquid chromatography (HPLC) were used to confirm the hemoglobin phenotype. Normal parental cell line, sickle clone, and two individual β-thalassemia clones were used to test the pharmacological induction of HbF. We initiated drug treatment in the expansion phase with 30 µM hydroxyurea. Trypan Blue staining and CD71/CD233/CD235 staining determined the effect of the drugs on the viability, growth rate and erythroid development of HUDEP2 lines. After 10 days of drug treatment, differentiated HUDEP2 were analyzed for globin expression through RT-qPCR and HPLC, and HbF positive cells (F-cells) were quantified via flow cytometry. Cells were placed at 2% O2 for four hours, fixed in glutaraldehyde, stained, and viewed under magnification to assess sickling potential. Results and Discussion: We generated multiple clones with biallelic sickle or β-thalassemia mutations. Sickle HUDEP2 clones almost exclusively expressed sickle hemoglobin with low level of HbF and hemoglobin A2 (HbA2), and β-thalassemia HUDEP2 clones produced no normal adult hemoglobin, 8-10% HbF, and 26-28% HbA2. On HPLC analysis, β-Thalassemia HUDEP2 clones had an unknown tall peak (39-45%) between HbF and HbA consistent with an α-globin homotetramer (α4). When subjected to hypoxic conditions for 4 hours, sickle HUDEP2 produced sickle cells. HUDEP2 parent cells did not sickle under hypoxic conditions. Hydroxyurea induced 3.8-fold, 1.8-fold, and 1.6-fold increases in γ-globin gene (HBG) expression; 2.9-fold, 1.4-fold, and 1.4-fold increases in the percentages of F-cells; 1.4-fold, 1.2-fold, and 1.6-fold increase in the percentages of HbF in sickle, K17X(A<T) and codon 6[-G] β-thalassemia HUDEP2 clones, respectively. No change was observed in CD71/CD235 positive HUDEP2 cells in the presence hydroxyurea. This finding demonstrated that hydroxyurea treatment induces HBG expression as well as HbF and F-cells in engineered sickle and β-thalassemia HUDEP2 clones. Future work will include screening other pharmacological compounds as well as studying the mechanism of HbF induction by using HUDEP2 clones. Conclusions: Our engineered sickle and β-thalassemia HUDEP2 cell lines have properties similar to those of patient erythroid cells and respond to the known HbF inducer hydroxyurea. This in vitro model system may facilitate the drug-discovery process by enabling multimodal drug screening on a large scale with consistent and reproducible results. Acknowledgments: This work was supported by the Cancer Prevention and Research Institute of Texas grants RR140081 and RP170721 (to G.B.) and the National Heart, Lung and Blood Institute of NIH (1K08DK110448 to V.S.) Disclosures No relevant conflicts of interest to declare.

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Alaribe, Chinwe S., Akolade R. Oladipupo, Naomi U. Kanu et Luca Rastrelli. « In vitro Antioxidant Activity of a Nigerian Propolis and Its Investigation on Sickle Red Blood Cells ». Ethiopian Pharmaceutical Journal 36, n^o 1 (3 novembre 2020) : 61–66. http://dx.doi.org/10.4314/epj.v36i1.7.

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Scientific evidence suggests that antioxidants could reduce the risk of chronic diseases, including cancer and cardiovascular diseases, and play an important role in general wellbeing. Sickle cell disease (SCD) is a debilitating monogenic disorder considered as a public health problem in many countries, but with a major burden in Sub-Saharan Africa. The use of antioxidants could prove relevant and beneficial in the treatment of SCD. In this study, the antioxidant and antisickling activities of methanol extract of a Nigerian propolis were investigated. Antioxidant activity was evaluated by scavenging effect against 1,1-diphenyl-2- picrylhydrazyl (DPPH) radical, and chelating effect against ferrous ions; ascorbic acid and thylenediamine tetraacetic acid (EDTA) were used, as standards, respectively. Antisickling activity was evaluated using a modified procedure of Emmel’s test, and phosphate buffered saline was used as a negative control. Compared to ascorbic acid (EC50 of 0.02 mg/ml), the propolis extract showed less scavenging effect (EC50 of 0.80 mg/ml) against DPPH radical. The propolis extract (EC50 of 1.84 mg/ml) also showed lower ferrous ion chelating activity compared to EDTA (EC50 of 0.29 mg/ml). In the antisickling assay, micrographic examination showed that, when treated with 1 mg/ml of the propolis extract, the morphology of the sickle red blood cells remained unaffected, thus indicating that the extract did not display antisickling effect at the concentration tested. These results indicate that the propolis extract possess moderate antioxidant activity and could be considered for possible application for its antioxidant benefits. Keywords: Nigerian propolis, oxidative stress, antioxidant activity, sickle cell disease, antisickling activity

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Helvaci, Mehmet Rami, Mustafa Sahan, Zeki Arslanoglu, Adnan Celikel, Orhan Ayyildiz et Orhan Ekrem Muftuoglu. « Atherosclerotic background of disseminated teeth losses in sickle cell diseases ». Journal of Medical Research 2, n^o 4 (25 août 2016) : 104–9. http://dx.doi.org/10.31254/jmr.2016.2407.

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Background: We tried to understand whether or not there is an atherosclerotic background of disseminated teeth losses in sickle cell diseases (SCDs). Methods: All patients with the SCDs were included, and cases with disseminated teeth losses (< 20 teeth present) were detected. Results: The study included 434 patients (222 males). Mean ages were similar in males and females (30.8 versus 30.3 years, respectively, P>0.05). Smoking (23.8% versus 6.1%) and alcohol (4.9% versus 0.4%) were higher in males (P<0.001 for both). Although the relatively younger mean ages, the prevalences of disseminated teeth losses were higher both in males and females (5.4% versus 1.4%, respectively, P<0.001). On the other hand, transfused units of red blood cells in their lives (48.1 versus 28.5, P=0.000), chronic obstructive pulmonary disease (25.2% versus 7.0%, P<0.001), ileus (7.2% versus 1.4%, P<0.001), cirrhosis (8.1% versus 1.8%, P<0.001), leg ulcers (19.3% versus 7.0%, P<0.001), digital clubbing (14.8% versus 6.6%, P<0.001), coronary artery disease (18.0% versus 13.2%, P<0.05), chronic renal disease (9.9% versus 6.1%, P<0.05), and stroke (12.1% versus 7.5%, P<0.05) were all higher in males. Conclusion: SCDs are chronic inflammatory processes on vascular endothelium particularly at the capillary level, and terminate with accelerated atherosclerosis induced end-organ failures in early years of life. Although the relatively younger mean ages of the study cases, the higher prevalences of disseminated teeth losses in both genders are probably due to the disseminated endothelial damage, inflammation, and fibrosis both at arterial and venous systems of the oral mucosa, periodontium, and teeth in the SCDs.

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El-Hawy, Mahmoud Ahmed, Samar Elsayed Tawfik El-Mistekawy, Noran Talaat Aboelkhair et Zeinab Sabri Abouzouna. « Comparison between serum nephrin and microalbuminuria as biomarkers for sickle cell nephropathy ». Pediatric Hematology/Oncology and Immunopathology 22, n^o 4 (20 décembre 2023) : 73–78. http://dx.doi.org/10.24287/1726-1708-2023-22-4-73-78.

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Sickle cell anemia is the most common monogenic blood disorder. The most common genotype is homozygous hemoglobin SS. Damage to red blood cells occurs due to changes in shape and function of the hemoglobin molecule inside it. This results in hemolytic anemia and the blockade of small blood vessels, which lead to vaso-occlusion and end organ failure. Sickle cell disease significantly alters renal structure and function and causes diverse renal diseases. To evaluate the validity of serum nephrin as a biomarker of sickle nephropathy and compare its sensitivity versus urinary microalbuminuria in the early detection of sickle cell nephropathy. This case control study was conducted on sixty patients suffering from sickle cell disease, 10 of them were diagnosed as sickle nephropathy, in addition to sixty apparently healthy children as a control group. Laboratory tests were hemoglobin electrophoresis, urinary microalbumin, serum ferritin, urea and creatinine. The glomerular filtration rate was estimated and serum nephrin was measured using enzymelinked immunosorbent assay. Among children with sickle cell anemia, 16.6% (10 patients) had sickle nephropathy diagnosed with elevated kidney function and low glomerular filtration rate. Liver and kidney function were significantly higher in cases with nephropathy than cases without nephropathy, while glomerular filtration rate was significantly lower in cases with nephropathy than cases without nephropathy. Serum nephrin was significantly higher in patients with nephropathy than patients without nephropathy versus non-significant difference regarding microalbuminuria level. The cutoff point for nephrin to diagnose sickle cell nephropathy was > 13 ng/mL versus 29.5 mg/dL for urinary microalbumin. Serum nephrin could be a valuable biomarker in early diagnosis of nephropathy in patients with sickle cell anemia.

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Chen, Shao-Yin, Yulei Wang, Marilyn I. Telen et Jen-Tsan A. Chi. « The Identification and Genomic Analysis of microRNAs in Human Erythrocytes in Sickle Cell Diseases. » Blood 110, n^o 11 (16 novembre 2007) : 3400. http://dx.doi.org/10.1182/blood.v110.11.3400.3400.

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Abstract Erythrocytes are circulating blood cells responsible for efficient gas exchange in human body. Since mature erythrocytes are terminally differentiated cells without nuclei and organelles, it is commonly thought that they do not contain nucleic acids. In this study, we re-examined this issue and found that human mature erythrocytes, while lacking ribosomal and large-sized RNAs, possess abundant small-sized RNAs. Using a combination of microarray analysis, real-time RT-PCR and Northern blots we found that mature erythrocytes contained abundant and diverse microRNAs which were distinct from microRNAs observed in reticulocytes/leukocytes and contributed to the majority of the microRNA expression in whole blood. When we used microarrays to analyze erythrocytes from normal (HbAA) and homozygous sickle (HbSS) individulas, we noted dramatic a difference in their microRNA expression pattern. To investigate how this difference is associated with erythrocyte disease phenotypes, we found that the poor expression of miR-320 was responsible for the defective downregulation of its target gene CD71 in HbSS cells during terminal differentiation. Collectively, we have discovered significant microRNA expression in human mature erythrocytes, which enables the microarray analysis of erythrocyte property to provide insights into the human erythrocyte diseases.

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Al-Sarraj, Faisal, Raed Albiheyri, Mohammed Qari, Mohammed Alotaibi, Majid Al-Zahrani, Yasir Anwar, Mashail A. Alghamdi et al. « Genetic Patterns of Oral Cavity Microbiome in Patients with Sickle Cell Disease ». International Journal of Molecular Sciences 25, n^o 16 (6 août 2024) : 8570. http://dx.doi.org/10.3390/ijms25168570.

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The Middle Eastern prevalence of sickle cell anemia, a genetic disorder that affects red blood cells, necessitates additional research. On a molecular level, we sought to identify and sort the oral microbiota of healthy individuals and those with sickle cell anemia. Furthermore, it is crucial to comprehend how changes in the genetic makeup of the oral microbiota impact the state of sickle cell anemia. Using next-generation sequencing, the 16S rRNA amplicon was examined using saliva samples from 36 individuals with sickle cell anemia and healthy individuals. These samples were obtained from sickle cell anemia patients (18 samples) and healthy control participants (controls, 18 samples). Various analyses are conducted using bioinformatic techniques to identify distinct species and their relative abundance. Streptococcus, followed by Fusobacterium nucleatum, Prevotella, and Veillonella were the most prevalent genera of bacteria in the saliva of the SCA and non-SCA individuals according to our findings. Rothia mucilaginosa, Prevotella scoposa, and Veillonella dispar species were the dominant species in both sickle cell anemia and non-sickle cell anemia subjects. Streptococcus salivarius, Actinomyces graevenitzii, Actinomyces odontolyticus, and Actinomyces georgiae spp. were the most prevalent bacterial spp. in the studied SCA cases. The sequencing of the 16S rRNA gene yielded relative abundance values that were visualized through a heatmap analysis. Alterations in the oral microflora’s constitution can significantly affect the susceptibility of sickle cell anemia patients to develop more severe health complications. Salivary diagnosis is a potential tool for predicting and preventing oral microbiome-related diseases in the future.

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Beri, Divya, Manpreet Singh, Marilis Rodriguez, Karina Yazdanbakhsh et Cheryl Ann Lobo. « Sickle Cell Anemia and Babesia Infection ». Pathogens 10, n^o 11 (4 novembre 2021) : 1435. http://dx.doi.org/10.3390/pathogens10111435.

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Babesia is an intraerythrocytic, obligate Apicomplexan parasite that has, in the last century, been implicated in human infections via zoonosis and is now widespread, especially in parts of the USA and Europe. It is naturally transmitted by the bite of a tick, but transfused blood from infected donors has also proven to be a major source of transmission. When infected, most humans are clinically asymptomatic, but the parasite can prove to be lethal when it infects immunocompromised individuals. Hemolysis and anemia are two common symptoms that accompany many infectious diseases, and this is particularly true of parasitic diseases that target red cells. Clinically, this becomes an acute problem for subjects who are prone to hemolysis and depend on frequent transfusions, like patients with sickle cell anemia or thalassemia. Little is known about Babesia’s pathogenesis in these hemoglobinopathies, and most parallels are drawn from its evolutionarily related Plasmodium parasite which shares the same environmental niche, the RBCs, in the human host. In vitro as well as in vivo Babesia-infected mouse sickle cell disease (SCD) models support the inhibition of intra-erythrocytic parasite proliferation, but mechanisms driving the protection of such hemoglobinopathies against infection are not fully studied. This review provides an overview of our current knowledge of Babesia infection and hemoglobinopathies, focusing on possible mechanisms behind this parasite resistance and the clinical repercussions faced by Babesia-infected human hosts harboring mutations in their globin gene.

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Oudrhiri, Noufissa, Frank Yates, Olivier Feraud, Emilie Gobbo, Cecile BAS, Dominique Luton, Pierre Francois Ceccaldi et al. « MODELING GENETIC Diseases through Reprogramming of HUMAN Amniotic Liquid Derived CELLS ». Blood 116, n^o 21 (19 novembre 2010) : 4789. http://dx.doi.org/10.1182/blood.v116.21.4789.4789.

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Abstract Abstract 4789 Pluripotency and self-renewal, two key characteristics of induced pluripotent stem cells (IPS), make these cells ideally suited for modeling diseases in vitro and generating biological resources usable for drug screening and cell therapy. However, the reprogramming efficiency of somatic cells greatly varies according to the cell type, to the in vitro proliferation index, the number of passages and the age of the donor. Human amniotic liquid-derived cells (hALDC), collected during amniocentesis for the prenatal diagnosis of genetic diseases, represent an abundant source of primary cells. In preliminary experiments we have shown that hALDC expressed endogenous Oct4 and Sox2 proteins suggesting that could be readily amenable to reprogramming. To this end, we have used two strategies using either hALDC or neonatal fibroblasts: (1) lentivirus mediated gene transfer of OCT4, SOX2, LIN28, NANOG, (2) retroviruses mediated gene transfer of OCT4, SOX2, CMYC, KLF4 and (3) lentiviral transfer of OCT4, SOX2. hALDC transduced by these viruses were placed on MEF and b-FGF (10 ng/ml) with daily medium changes. One to three weeks after infection, typical human ES-like colonies could be picked up for expansion before being characterized. HALDC show an increased reprogramming potential with the [OCT4, SOX2, LIN28, NANOG] and [OCT4, SOX2] cocktails, when compared to reprogramming of neonatal fibroblasts. Twelve hALDC-derived-IPS cells were obtained from 12 different samples of amniotic fluid. All hALDC-IPS cell lines maintained a normal karyotype in culture and displayed the morphology and characteristics of human embryonic stem cells, including the surface expression of Tra-160, SSEA-3, SSEA-4, HESCA-1 and alkaline phosphatase, and formed multi-lineaged teratomas upon injection to NOD-SCID mice. Gene expression profiles of the IPS cell lines reveal a high correlation coefficient between hALDC-iPS cells and human embryonic stem cells, and a low correlation between hALDC-iPS and hALDC. When compared to hES cells H1, H9 and Cl01, these cell lines generated hematopoiesis with a variable efficiency in vitro. Amongst the hALDC-IPS cell lines generated by our laboratory (http://www.hescreg.eu/) four lines carry an inherited trisomy of chromosome 21, and three lines carry the homozygous “S” mutation in the beta-globin gene of sickle-cell anemia. All hALDC-IPS cell are currently banked at the Human Pluripotent Stem Cell Core Facility, France. In conclusion, hALDC can be rapidly and efficiently reprogrammed to pluripotency with a limited number of transgenes. Moreover, hALDC-IPS cell lines derived from patients can be used to modelize in vitro the phenotypic features of monogenic diseases such as sickle cell anemia or more complex, multifactorial disorders such as Down's syndrom. The ability to generate hematopoietic differentiation from these cell lines will facilitate the modelling of these hematopoietic disorders. Disclosures: No relevant conflicts of interest to declare.

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Orjih, Augustine U., Coy D. Fitch et Rekha Chevli. « Toxic Heme in Sickle Cells : an Explanation for Death of Malaria Parasites * ». American Journal of Tropical Medicine and Hygiene 34, n^o 2 (1 mars 1985) : 223–27. http://dx.doi.org/10.4269/ajtmh.1985.34.223.

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Magnani, John L., Arun Sarkar, Yonhong Li, Scarlett Goon, Bea Wagner, Jungshan Chang, Beat Ernst, Paul S. Frenette et John T. Patton. « GMI-1070 : A Small Pan-Selectin Antagonist That Inhibits Leukocyte Adhesion and Migration in Multple Disease Models In Vivo. » Blood 110, n^o 11 (16 novembre 2007) : 2410. http://dx.doi.org/10.1182/blood.v110.11.2410.2410.

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Abstract Rational design of glycomimetic inhibitors based on the bioactive conformation of functional carbohydrates provides new therapeutic opportunities for the development of small molecule drugs with improved activity, pharmacokinetics, and bioavailability relative to native ligands. In designing more active glycomimetic selectin inhibitors, the low enthalpy (ΔH0) of the reaction is compensated by pre-forming the bioactive conformation thereby improving the entropy (ΔS0), known as S/H compensation. Modifications of the molecule that also stabilize the core structure, further improve ΔS0 and binding activity. To improve ΔH0, second site interactions were explored. To address the requirements for P and L-selectins, interactions were combined for both carbohydrate and sulfate-binding domains to produce heterobifunctional molecules. By stabilizing the bioactive core and exploring second site molecular interactions, we have produced a family of pan-selectin antagonists, one of which (GMI-1070) is now in development and scale-up synthesis as a lead compound. GMI-1070 is a potent inhibitor of E, P, and L-selectins in vitro and inhibits E and P-selectin-mediated leukocyte adhesion to endothelial monolayers under flow conditions. More importantly, GMI-1070 is active in several animal models of diseases requiring leukocyte adhesion and migration such as: a delayed-type hypersensitivity (DTH) response, cardiac ischemia/reperfusion injury, and vaso-occlusive crisis in sickle cell disease. GMI-1070 significantly inhibited infarct size in an ischemia/reperfusion cardiac injury model in rats. A single dose at 10mg/kg gave maximal inhibition. The effects of GMI-1070 on T-cell migration was studied in a DTH model. Mice were sensitized with oxazolone on the abdomen and then, 7 days later challenged on the ear. Donors T-cells from a different cohort of similarly sensitized mice were fluorescently labeled and injected into the test cohorts at the time of administration of GMI-1070. Three hours following injection, migration of fluorescent T-cells to the challenged area was determined. Selectin-dependent T-cell migration in the DTH response was completely eliminated with a dose of 10mg/kg of GMI-1070, suggesting the potential clinical application in diseases involving skin homing T-cells such as graft vs. host disease (GVHD) after bone marrow transplantation, and other inflammatory skin diseases. We have also shown that acute myelogenous leukemia (AML) cells adhere to endothelial cells under flow in a selectin-dependent mechanism suggesting that graft vs. leukemia as well as graft vs. host may be affected by treatment with GMI-1070. GMI-1070 was also tested in a model of vaso-occlusive crisis in sickle cell disease using Berkeley sickle cell mice. Blood flow was restored to normal values and adhesion of sickle red blood cells to adherent leukocytes was essentially eliminated as determined intravital microscopy using a dose of 20mg/kg administered at the time of elicitation of the vaso-occlusive challenge (TNFα) and at the start of intravital microscopy (70 minutes later). Based on the encouraging results in disease models, we are advancing the clinical development of GMI-1070 into Phase 1 studies to support indications which include the treatment of sickle cell patients in vaso-occlusive crisis.

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Zedde, Marialuisa, Micol Quaresima, Isabella Capodanno, Ilaria Grisendi, Federica Assenza, Manuela Napoli, Claudio Moratti et al. « Neurovascular Manifestations of Sickle Cell Disease ». Hemato 5, n^o 3 (9 août 2024) : 277–320. http://dx.doi.org/10.3390/hemato5030023.

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Sickle cell disease (SCD) is a hereditary blood disorder characterized by abnormal hemoglobin, leading to the sickle shape of red blood cells. It has several vascular complications and the cerebrovascular ones are among the most frequent and severe both in children and in adults. This review summarizes the main neurovascular manifestations of SCD, including acute stroke, silent cerebral infarction, large-vessel diseases (moyamoya arteriopathy and aneurysms), and brain bleeding. Both epidemiology, pathophysiology, and treatment issues are addressed and prevention of cerebrovascular events, including silent cerebral infarctions, is particularly relevant in SCD patients, being associated to poor functional outcome and cognitive complaints. Transfusions and hydroxyurea are the main available therapy at the moment, but contraindications, availability, and complications might prevent their long term use, particularly in low-income countries. The role of transcranial Doppler in monitoring the patients (mainly children) is analyzed and a practical approach has been selected in order to give the main messages from the current literature for a better management of SCD patients.

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Chattopadhyay, Ranjanee. « Generation and clinical applications of stem cells in regenerative medicines ». Journal of Applied and Natural Science 16, n^o 4 (20 décembre 2024) : 1417–30. https://doi.org/10.31018/jans.v16i4.5886.

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Since the discovery of stem cells, they have been claimed to be nature’s miracle due to their unique properties, which set them apart from other cell types. It has fascinated the world with its myriad of opportunities in regenerative medicine, such as treating blood-borne cancers, neurodegenerative diseases and disorders, immune system diseases, heart diseases, etc. Although Stem Cell Therapy is yet to be commercialized in India, research and clinical trials using Hematopoietic Stem Cell Transplantation are being conducted to understand the efficacy of stem cells in the remission of various malignant and non-malignant diseases such as Thalassemia, Acute Lymphoblastic Leukemia, Sickle Cell Disease, Aplastic Anemia, Hodgkin’s Lymphoma and Juvenile Rheumatoid Arthritis among other diseases. Stem cell research has bloomed over the years and has demonstrated immense potential in Embryonic Stem Cell Therapy, Somatic Stem Cell Therapy, Induced Pluripotent Stem Cell Therapy and, with further understanding of stem cells, it could also be applied in drug modelling and drug development, skin replacement and regeneration, organ repair and regeneration and disease modelling for drug testing, revolutionizing the healthcare industry in the future. The present review discusses the research on stem cells, their applications in regenerative medicine, and economic, regulatory and ethical concerns.

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Rami Helvaci, Mehmet, Valeria Pappel, Kubra Piral, Mehpare Camlibel, Huseyin Sencan, Ramazan Davran, Mustafa Yaprak, Abdulrazak Abyad et Lesley Pocock. « Atherosclerotic Background of Chronic Obstructive Pulmonary Disease in Sickle Cell Diseases ». Universal Library of Medical and Health Sciences 01, n^o 01 (15 décembre 2023) : 04–18. http://dx.doi.org/10.70315/uloap.ulmhs.2023.0101002.

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Background: Sickle cell diseases (SCDs) are inborn and catastrophic processes on vascular endothelium, particularly at the capillaries. Methods: All patients were included. Results: We studied 222 males and 212 females with similar mean ages (30.8 vs 30.3 years, p>0.05, respectively). Beside chronic obstructive pulmonary disease (COPD) (25.2% vs 7.0%, p<0.001), smoking (23.8% vs 6.1%, p<0.001), alcohol (4.9% vs 0.4%, p<0.001), transfused red blood cells (RBCs) in their lives (48.1 vs 28.5 units, p=0.000), disseminated teeth losses (5.4% vs 1.4%, p<0.001), ileus (7.2% vs 1.4%, p<0.001), cirrhosis (8.1% vs 1.8%, p<0.001), leg ulcers (19.8% vs 7.0%, p<0.001), digital clubbing (14.8% vs 6.6%, p<0.001), coronary heart disease (CHD) (18.0% vs 13.2%, p<0.05), chronic renal disease (CRD) (9.9% vs 6.1%, p<0.05), and stroke (12.1% vs 7.5%, p<0.05) were all higher, and autosplenectomy (50.4% vs 53.3%, p<0.05) and mean age of mortality were lower in males, significantly (30.2 vs 33.3 years, p<0.05). Conclusion: The hardened RBCs-induced capillary endothelial damage initiates at birth, and terminates with multiorgan failures even at childhood. Parallel to COPD, all of the atherosclerotic risk factors or consequences including smoking, alcohol, disseminated teeth losses, ileus, cirrhosis, leg ulcers, digital clubbing, CHD, CRD, and stroke were higher, and autosplenectomy and mean age of mortality were lower in males which can not be explained by effects of smoking and alcohol alone at the relatively younger mean age. So autosplenectomy may be a good whereas male gender alone may be a bad prognostic factor, and COPD may have an atherosclerotic background in the SCDs.

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Panda, Harit, Huaichun Wen, Mikiko Suzuki et Masayuki Yamamoto. « Multifaceted Roles of the KEAP1–NRF2 System in Cancer and Inflammatory Disease Milieu ». Antioxidants 11, n^o 3 (11 mars 2022) : 538. http://dx.doi.org/10.3390/antiox11030538.

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In a multicellular environment, many different types of cells interact with each other. The KEAP1–NRF2 system defends against electrophilic and oxidative stresses in various types of cells. However, the KEAP1–NRF2 system also regulates the expression of genes involved in cell proliferation and inflammation, indicating that the system plays cell type-specific roles. In this review, we introduce the multifarious roles of the KEAP1–NRF2 system in various types of cells, especially focusing on cancer and inflammatory diseases. Cancer cells frequently hijack the KEAP1–NRF2 system, and NRF2 activation confers cancer cells with a proliferative advantage and therapeutic resistance. In contrast, the activation of NRF2 in immune cells, especially in myeloid cells, suppresses tumor development. In chronic inflammatory diseases, such as sickle cell disease, NRF2 activation in myeloid and endothelial cells represses the expression of proinflammatory cytokine and adherent molecule genes, mitigating inflammation and organ damage. Based on these cell-specific roles played by the KEAP1–NRF2 system, NRF2 inducers have been utilized for the treatment of inflammatory diseases. In addition, the use of NRF2 inducers and/or inhibitors with canonical antineoplastic drugs is an emerging approach to cancer treatment.

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Conran, Nicola, et Lidiane Torres. « cGMP modulation therapeutics for sickle cell disease ». Experimental Biology and Medicine 244, n^o 2 (28 janvier 2019) : 132–46. http://dx.doi.org/10.1177/1535370219827276.

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Sickle cell disease (SCD) is an inherited disease caused by the production of abnormal hemoglobin (Hb) S, whose deoxygenation-induced polymerization results in red blood cell (RBC) sickling and numerous pathophysiological consequences. SCD affects approximately 300,000 newborns worldwide each year and is associated with acute and chronic complications, including frequent painful vaso-occlusive episodes that often require hospitalization. Chronic intravascular hemolysis in SCD significantly reduces vascular nitric oxide (NO) bioavailability, consequently decreasing intracellular signaling via cyclic guanosine monophosphate (cGMP), in turn diminishing vasodilation and contributing to the inflammatory mechanisms that trigger vaso-occlusive processes. Oxidative stress may further reduce NO bioavailability in SCD and can oxidize the intracellular enzyme target of NO, soluble guanylate cyclase (sGC), rendering it inactive. Increasing intracellular cGMP-dependent signaling constitutes an important pharmacological therapeutic approach for SCD with a view to augmenting vasodilation, and reducing inflammatory mechanisms, as well as for increasing the production of anti-polymerizing fetal Hb in erythroid cells. Pharmacological agents under pre-clinical and clinical investigation for SCD include NO-based therapeutics to augment NO bioavailability, as well as heme-dependent sGC stimulators and heme-independent sGC activators that directly stimulate native and oxidized sGC, respectively, therefore bypassing the need for vascular NO delivery. Additionally, the phosphodiesterases (PDEs) that degrade intracellular cyclic nucleotides with specific cellular distributions are attractive drug targets for SCD; PDE9 is highly expressed in hematopoietic cells, making the use of PDE9 inhibitors, originally developed for use in neurological diseases, a potential approach that could rapidly amplify intracellular cGMP concentrations in a relatively tissue-specific manner. Impact statement Sickle cell disease (SCD) is one of the most common inherited diseases and is associated with a reduced life expectancy and acute and chronic complications, including frequent painful vaso-occlusive episodes that often require hospitalization. At present, treatment of SCD is limited to hematopoietic stem cell transplant, transfusion, and limited options for pharmacotherapy, based principally on hydroxyurea therapy. This review highlights the importance of intracellular cGMP-dependent signaling pathways in SCD pathophysiology; modulation of these pathways with soluble guanylate cyclase (sGC) stimulators or phosphodiesterase (PDE) inhibitors could potentially provide vasorelaxation and anti-inflammatory effects, as well as elevate levels of anti-sickling fetal hemoglobin.

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Lamba, S. S., K. Y. Such et H. Lewis Ill. « The Potential Use of Hydroxyurea as Treatment for Sickle Cell Disease ». Current Medicinal Chemistry 1, n^o 5 (février 1995) : 366–75. http://dx.doi.org/10.2174/092986730105220216101649.

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Abstract: Recent biochemical and biophysical studies of sickle cell hemoglobin have provided valuable insight into the molecular basis of the sickling phenomenon in sickle cell disease. A large number of compounds have been examined for antisickling potential. These can be characterized as noncovalent or covalent in their mechanism of action. Examples of noncovalent agents include: alkylureas, dimethyl sulfoxide, dimethylforma mide, small peptides, etc. Examples of covalent agents include: nitrogen mustard, glyceraldehyde, aldehydic pyridoxal derivatives, dimethyladipimidate, etc. Also, acylating agents such as acylsalicylates have been investigated. lnspite of such advances and attempts, a useful agent has not been successfully produced. Thus, sickle cell disease continues to be a serious health problem for which there is no cure, and the treatment remains to be symptomatic. Sickle cell disease includes a group of hereditary hemoglobin disorders characterized by red cells which undergo sickle shape transformation under hypoxic conditions. Due to the substitution of valine for glutamic acid in position 6 of the beta chain, sickle hemoglobin polymerizes when it is deoxygenated. The most clinically significant of these diseases is sickle cell anemia. Symptoms include dactylitis, painful crisis, splenic sequestration and the development of multi-organ damage and failure. Different clinical presentations of sickle cell anemia call for individualized management. The reason for such clinical variability is not known; although the patient's hemoglobin level as well as fetal hemoglobin (HbF) concentrations are important. New therapeutic approaches include the use of hydroxyurea which is reported to increase the level of fetal hemoglobin which interferes with polymer formation. Because fetal hemoglobin contains gammaglobin chains instead of beta chains, it is not affected by the genetic defect that causes sickle cell disease. Increased levels of fetal hemoglobin decrease the tendency toward intracellular polymerization of sickle hemoglobin that characterizes the disease. This review provides information regarding the role of fetal hemoglobin (HbF) and sickling; methodology for an accurate quantitation of HbF; recent pharmacological interventions; and includes results of selected clinical trials reported in recent years.

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Calzolari, Roberta, Aurelio Maggio, Alice Pecoraro, Vito Borruso, Antonio Troia, Santina Acuto, Danilo D’Apolito, Leda Ferro et Rosalba Di Marzo. « Hydroxyurea-Mediated Reactivation of Fetal Genes in Primary Erythroid Cell Cultures from Beta-Thalassemia Patients. » Blood 108, n^o 11 (16 novembre 2006) : 3809. http://dx.doi.org/10.1182/blood.v108.11.3809.3809.

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Abstract Fetal hemoglobin (HbF) is frequently increased in the hemoglobinopathies such as sickle cell anemia and b-thalassemia. Epidemiological studies have indicated that an increase in HbF ameliorates the clinical symptoms of these diseases (Rodgers and Rachmilewitz - Bri J. Haemat. 91: 263 -1995). In sickle cell anemia, HbF containing red blood cells have a lower concentration of sickle hemoglobin (HbS), and the HbF itself inhibits HbS polymerization, decreasing cell sickling process (Eaton and Hofrichter - Science 268:1142 -1995). In b-thalassemia patients, HbF partially compensate HbA deficiency and could potentially improve RBC survival resulting in an increase of hemoglobin levels. Hydroxyurea (HU) is one of the pharmacological agents currently used to stimulate HbF synthesis in patients with sickle cell anemia and more recently has been tested in clinical trials for b-thalassemia patients too (Olivieri et al. Ann. NY Acad Sci850:100-1998; Rigano et al. Hemogl.21(3): 219- 1997; Dixit et al. Ann. Haematol. 84: 441 -2005). The mechanism involved in the HU-mediated changes is still unclear. It may involve a selection of a minor pre-existing subpopulation of F-cells that has a growth and/or survival advantage (cellular mechanism). This mechanism may be particularly effective for cells derived from patients with hemoglobinopathies, where F-cells may be resistant to “ineffective erythropoiesis”. An alternative mechanism could involve stimulation of HbF in all or the majority of cell-population by direct induction of g genes (molecular mechanism). Here we report the analysis on thalassemia patients homozygoutes for Lepore genotype that present high levels of fetal hemoglobin. We combined the use of primary erythroid cell culture from peripheral blood stem cells of these patients, with primary transcript in situ hybridization (RNA-FISH) of the g and b globin genes to investigate the mechanism of action of hydroxyurea in adult erythroid cells. RNA-FISH on erythroid cell cultures from these patients reveals that the majority of cells express one g allele only (g: 75.2 %, g:g 19.6%). The analysis in hydroxyurea-treated cultures shows the increase of cells transcribing both g-alleles, indicating the reactivation of fetal genes (g: 58.1%, g:g 40%). This evidence suggests that the molecular mechanism is involved directly on fetal genes reactivation to increase fetal hemoglobin production in HU-treated patients.

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Renó, Cristiane Oliveira, Grazielle Aparecida Silva Maia, Leilismara Sousa Nogueira, Melina de Barros Pinheiro, Danyelle Romana Alves Rios, Vanessa Faria Cortes, Leandro Augusto de Oliveira Barbosa et Hérica de Lima Santos. « Biochemical Evaluation of the Effects of Hydroxyurea in Vitro on Red Blood Cells ». Antioxidants 10, n^o 10 (12 octobre 2021) : 1599. http://dx.doi.org/10.3390/antiox10101599.

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Hydroxyurea (HU) is a low-cost, low-toxicity drug that is often used in diseases, such as sickle cell anemia and different types of cancer. Its effects on the red blood cells (RBC) are still not fully understood. The in vitro effects of HU were evaluated on the biochemical parameters of the RBC from healthy individuals that were treated with 0.6 mM or 0.8 mM HU for 30 min and 1 h. After 30 min, there was a significant increase in almost all of the parameters analyzed in the two concentrations of HU, except for the pyruvate kinase (PK) activity. A treatment with 0.8 mM HU for 1 h resulted in a reduction of the levels of lipid peroxidation, Fe3+, and in the activities of some of the enzymes, such as glutathione reductase (GR), glucose-6-phosphate dehydrogenase (G6PD), and PK. After the incubation for 1 h, the levels of H2O2, lipid peroxidation, reduced glutathione (GSH), enzymatic activity (hexokinase, G6PD, and superoxide dismutase (SOD) were reduced with the treatment of 0.8 mM HU when compared with 0.6 mM. The results have suggested that a treatment with HU at a concentration of 0.8 mM seemed to be more efficient in protecting against the free radicals, as well as in treating diseases, such as sickle cell anemia. HU appears to preferentially stimulate the pentose pathway over the glycolytic pathway. Although this study was carried out with the RBC from healthy individuals, the changes described in this study may help to elucidate the mechanisms of action of HU when administered for therapeutic purposes.

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Boopalan, Dinesh, Ramanan Pandian et Gokul Kesavan. « Prospects for Stem Cell-Based Regenerative Therapies in India ». StemJournal 3, n^o 1 (17 juin 2021) : 11–21. http://dx.doi.org/10.3233/stj-210002.

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Stem cells offer a promising therapeutic strategy to not only treat several incurable diseases but also regenerate damaged tissues. The current global boom in the field of stem cell and regenerative therapies had led to India becoming a global hotspot for stem cell-based therapies. In this review, we assess the current status of stem cell therapy trials in India and show that the bone marrow-derived stem cells, like mesenchymal stem/stromal cells (MSCs), are predominantly used. Phase 1 and 2 clinical trials have also used MSCs to alleviate symptoms of severe novel coronavirus infections. Recent breakthroughs in gene editing technologies, combined with stem cell therapy, can be effectively harnessed to devise large-scale and affordable treatments for haematological diseases that are highly prevalent in India, like beta-thalassemia and sickle cell diseases. Innovations in stem cell therapy in India can make treatments more affordable to address the needs of in-country patients.

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Chang Milbauer, Liming, Peng Wei, Judy Enenstein, Aixiang Jiang, Cheryl A. Hillery, J. Paul Scott, Stephen C. Nelson et al. « Genetic endothelial systems biology of sickle stroke risk ». Blood 111, n^o 7 (1 avril 2008) : 3872–79. http://dx.doi.org/10.1182/blood-2007-06-097188.

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Abstract Genetic differences in endothelial biology could underlie development of phenotypic heterogeneity among persons afflicted with vascular diseases. We obtained blood outgrowth endothelial cells from 20 subjects with sickle cell anemia (age, 4-19 years) shown to be either at-risk (n = 11) or not-at-risk (n = 9) for ischemic stroke because of, respectively, having or not having occlusive disease at the circle of Willis. Gene expression profiling identified no significant single gene differences between the 2 groups, as expected. However, analysis of Biological Systems Scores, using gene sets that were predetermined to survey each of 9 biologic systems, showed that only changes in inflammation signaling are characteristic of the at-risk subjects, as supported by multiple statistical approaches. Correspondingly, subsequent biologic testing showed significantly exaggerated RelA activation on the part of blood outgrowth endothelial cells from the at-risk subjects in response to stimulation with interleukin-1β/tumor necrosis factorα. We conclude that the pathobiology of circle of Willis disease in the child with sickle cell anemia predominantly involves inflammation biology, which could reflect differences in genetically determined endothelial biology that account for differing host responses to inflammation.

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Asakura, Toshio, Jisheng Yang, Qiukan Chen, Greg Evans et Osheiza Abdulmalik. « New Approach for Finding Novel Antisickling Agents at the NIH NHLBI Sickle Cell Disease Reference Laboratory. » Blood 108, n^o 11 (16 novembre 2006) : 1219. http://dx.doi.org/10.1182/blood.v108.11.1219.1219.

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Abstract Although numerous antisickling agents that chemically bind with sickle hemoglobin (Hb S) and inhibit sickling of sickle erythrocytes (SS cells) in vitro were reported and some of them were brought to clinical trials, none were satisfactory for clinical use. The major problem with this type of drugs is the difficulty of delivering a sufficient amount of antisickling drug to intracellular Hb S because:chemicals that bind with the side chains of hemoglobin also bind with the side chains of other proteins in the gastrointestinal tract, blood and red blood cells (RBCs) prior to binding with intracellular Hb S; andthe concentration of Hb S in SS cells is very high (5 mM of tetrameric Hb S, 20 mM of Hb subunits, or a total amount of approximately 500 grams of Hb S in an adult patient), and the amount of chemical that reaches SS cells upon oral administration cannot modify a significant portion of Hb S to inhibit sickling of SS cells. For these reasons, drugs that chemically bind with Hb S including those that form Schiff base adducts with Hb S seem to have no clinical value. We found that certain aromatic aldehydes that bind with Hb S allosterically do not have these problems. Since these compounds combine with Hb S physically like a key-and-lock relationship, a low concentration (such as less than 2 mM) of such compound in the blood can bind with a large portion of intracellular Hb S, shift the oxygen equilibrium curve toward the left and inhibit sickling of SS cells (Brit. J. Hematol.128:552–561, 2005). This type of allosteric binding between aromatic aldehydes and Hb is analogous to the binding between 2,3-diphosphoglycerate and Hb. Quite interestingly, our investigations indicate that NIPRISAN (NICOSAN), an herbal medicine that shows a strong antisickling effect both in vitro and in vivo (in transgenic sickle mice) (Brit. J. Haematol.118:337–343, 2002; Brit. J. Haematol.122:1001–1008 2003), contains various aromatic aldehydes (unpublished data). Allosteric drugs designed to interact with specific proteins in the body may be useful as a new type of therapeutic modality for the treatment of sickle cell disease and other diseases. [Researchers with candidate drugs that may have beneficial effects for SCD are welcome to contact the SCD Reference Laboratory for free in vitro evaluation of their agents (for more information, please see our website at www.tatcom.com/sickle-cell).

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Augustine O. Odibo, Ifunanya R. Akaniro et Emmanuel M. Ubah. « In vitro investigation of the antisickling properties of aqueous fruits extracts of Citrus paradisi, Musa acuminata and Malus domestica ». GSC Biological and Pharmaceutical Sciences 13, n^o 3 (30 décembre 2020) : 203–9. http://dx.doi.org/10.30574/gscbps.2020.13.3.0412.

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Sickle cell disease (SCD) is a genetic blood disorder that affects the shape and transportation of red blood cells (RBCs) in blood vessels, leading to various clinical complications. Many drugs that are available for treating the disease are insufficiently effective, toxic, or too expensive. Therefore, there is a pressing need for safe, effective, and inexpensive therapeutic agents from indigenous plants used in ethnomedicine. In the current study, the potentials of aqueous extracts of Citrus paradisi, Musa acuminata, Malusdomestica fruit in sickle cell disease management were investigated in vitro using P-hydroxybenzoic acid and normal saline as positive and negative control respectively. The method employed the inhibition of sodium metabisulphite induced sickling of HbSS red blood cells, collected from confirmed sickle cell patients. Results obtained showed that; 50 mg/ml aqueous extract of Musa acuminata showed the lowest sickling inhibition (80.3%) at 60 minutes while 1 mg/ml gave the highest inhibition of 97.3% at 90 minutes. For Citrus paradisi, lowest (83.3%) and highest (98%) sickling inhibitions were obtained with 25 mg/ml and 50 mg/ml fruit extracts at 30 minutes and 60 minutes respectively. Malus domestica had the highest antisickling activities of 99% and 99.33% respectively at 30 and 60 minutes. In all, the sickling inhibition was least with Musa acuminata but highest with Malus domestica. Also, highest inhibitions were observed at 60 minutes (optimum time) and 10 mg/ml (optimum concentration). This study has demonstrated that; Malus domestica, Citrus paradisi and Musa acuminata possess antisickling potentials useful in the management or therapy of sickle cell diseases.

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Mannino, Robert, David R. Myers, Yumiko Sakurai, Russell E. Ware, Gilda Barabino et Wilbur Lam. « Increased Erythrocyte Rigidity Is Sufficient to Cause Endothelial Dysfunction in Sickle Cell Disease ». Blood 120, n^o 21 (16 novembre 2012) : 818. http://dx.doi.org/10.1182/blood.v120.21.818.818.

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Abstract Abstract 818 Endothelial dysfunction is a major component of sickle cell disease (SCD) pathophysiology. Interestingly, previous cardiovascular research has definitively shown that endothelial cells biologically respond to mechanical forces and aberrations in these forces cause endothelial dysfunction via pro-inflammatory pathways that are also involved in SCD. While endothelial dysfunction in SCD has been well characterized biologically, little research has focused on the direct biophysical effects of SCD blood on endothelium. As endothelial cells are in constant contact with flowing “stiffened” sickle erythrocytes, we propose that the direct mechanical interactions between the physically altered sickle erythrocytes and endothelial cells are an additional cause of endothelial dysfunction in SCD (Figure 1A). Endothelial dysfunction in SCD is thought to be caused by the downstream effects of vaso-occlusion and/or hemolysis. Our laboratory has recently developed and published a description of an in vitro microvasculature model comprised of endothelial cells that are cultured throughout the entire 3D inner surface of a microfluidic system designed for investigating cellular interactions in hematologic diseases (Tsai, et al, JCI, 2012), (Figure 1B-D). This microvasculature-on-a-chip recapitulates an ensemble of physiological processes and biophysical properties, including adhesion molecule expression, blood cell-endothelial cell interactions, cell deformability, cell size/shape, microvascular geometry, hemodynamics, and oxygen levels (Myers et al. JoVE, 2012), all of which may contribute to endothelial dysfunction in SCD. We hypothesize that the mechanical interactions between sickle erythrocytes and endothelial cells alone are sufficientto cause endothelial dysfunction in our microvasculature-on-a-chip. To test our hypothesis, we flowed different suspensions of healthy red blood cells (RBCs), and stiffened RBCs, through our microvasculature on a chip cultured with HUVECs. We suspended fresh human RBCs in media at a low hematocrit recapitulating the anemic conditions typically seen in SCD patients as a control. The experimental conditions used the same solution as the control, but also contained glutaraldehyde-stiffened RBCs, which are of the same stiffness as irreversibly sickled cells (ISCs), at approximately the same concentrations as ISCs in SCD patients. The stiffened RBC suspension was washed multiple times to eliminate all traces of glutaraldehyde and to ensure that any endothelial cell dysfunction in our system was due to mechanical effects between the endothelium and RBCs. After 4 hours of perfusion, the number of occlusions in our microsystem was counted and the cells were fixed and stained for Vascular Cell Adhesion Molecule 1 (VCAM-1). VCAM-1 been shown to be a marker of endothelial cell dysfunction and is a biomarker for severe vasculopathy in SCD (Dworkis, Am J Hematol, 2011). Immunofluorescence staining in our microsystem confirmed that VCAM1 is upregulated (Figure 2) in HUVECs when exposed to flowing stiffened RBCs compared to control RBCs. VCAM-1 upregulation appears to be diffuse throughout the length of the device. After experimentation, endothelial cells in our system can be isolated for further RT-PCR or microarray analysis. As such, ongoing work involves investigating and quantifying the expression of other pro-inflammatory molecules to elucidate the underlying mechanisms of this biomechanical process involving RBCs and endothelial cells. Additional experiments complementary experiments using endothelial cells from other anatomic areas, SCD patient samples, and murine SCD models are also underway. Our data indicates that purely physical interactions between endothelial cells and stiffened RBCs are sufficient to cause some degree of endothelial dysfunction, even in the absence of vaso-occlusion, ischemia, or oxidative stress due to hemolysis. As sickle RBCs and ISCs are constantly circulating in the blood of SCD patients, our results have profound implications for SCD pathophysiology and may help explain why SCD patients develop chronic diffuse vasculopathy over time. Disclosures: No relevant conflicts of interest to declare.

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Sanjeevi, Aditya, Aniket Vijay Rao, Samikchhya Keshary Bhandari, Daniel Idoate Jose Domench et Himal Kharel. « Hidden Dangers : Pulmonary Embolism Risk in Sickle Cell Trait - Insights from the NIS Database 2020 ». Blood 144, Supplement 1 (5 novembre 2024) : 2498. https://doi.org/10.1182/blood-2024-212129.

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Background: Sickle cell trait is a genetic condition that occurs when an individual inherits a gene for normal hemoglobin (HbA) and a gene for sickle hemoglobin (HbS). Patients are usually asymptomatic and are diagnosed through screening tests followed by genetic analyses. In this study, we aim to compare the incidence of PE in patients with sickle trait and those without it to determine if sickle cell trait increased the risk of development of PE. Methods: We conducted a retrospective analysis of the NIS database 2020 with an International Classification of Diseases (ICD)-10 code for sickle cell trait, PE and other comorbid conditions. STATA version SE 18.0 was used for statistical analysis. We used multivariate logistic regression models adjusting for demographic characteristics and comorbidities to determine the odds of developing PE in patients with sickle cell trait in comparison to those without it. Results: During our study period, we noted a total number 31,766,068 hospitalizations out of which sickle cell trait hospitalizations accounted for 56,195. The median age of patients with sickle cell trait hospitalizations was 35.6 years (95% CI 35.05-36.33) and there was a female predominance. 56.39% of the patients with a sickle cell trait related hospitalization had a Charlson Comorbidity Index (CCI) of 56.39%, 17.75% had a CCI 1, 7.48% had a CCI of 2 and 18.38% had a CCI of 3. The total number of PE cases noted in the group without sickle cell trait was 181,565 while the number of PE cases in patient with sickle cell trait was 455 during the study period. We did a subgroup analysis in patients with sickle cell trait related hospitalization after adjusting for age, gender, race, CCI and the risk factors for PE such as smoking, oral contraceptive intake, obesity, history of thrombosis, thrombophilia, cancer, myeloproliferative neoplasms, fracture, COPD, and varicose veins using multivariate regression analysis. This revealed that the sickle cell trait group had higher odds of developing PE with an aOR - 1.56 (95% CI 1.26-1.94, p<0.001) Conclusions: Our study shows that patients with sickle cell trait are at significantly increased odds of developing PE in comparison to patients without the trait. While this highlights the heightened thrombotic risk associated with sickle cell trait, we must also appreciate the fact that thus far the mechanism by which this happens is poorly understood. One proposed mechanism is tPA resistance induced by sickle cells indicating a complex interplay between various blood cell types. Further studies are needed to explore the role of sickle cell trait as a risk factor in adverse health outcomes.

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Aula Ibrahim Abd-Alrazzaq et Afifa Radha Aziz. « Effectiveness of An Educational Program on Mother’s Knowledge toward their Children with Sickle Cell Anemia about Non-Pharmacological Approaches to Pain Management in Basra Center for Hereditary Blood Diseases ». Indian Journal of Forensic Medicine & ; Toxicology 15, n^o 3 (17 mai 2021) : 831–38. http://dx.doi.org/10.37506/ijfmt.v15i3.15413.

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Background: Sickle cell anemia is a chronic disease and a blood disorder that induces cellular modification to the sickle-shaped form of defective hemoglobin in red blood cells. It is the most common genetic blood disease in the world. For people with sickle cell disease, it is important to explore non pharmacological treatments and use them as alternatives to drug treatments to relieve and treat acute and chronic pain. Methodology: A descriptive (quasi experimental) design. This study used a pretest, posttest I and posttest II with a design that is used is the one group. A non- probability sample of (30) mother was chose. Result: The findings of the study indicated that there was high significant difference among mother’s knowledge pretest and posttest I and posttest II at p-value =0.001. That indicates the effectiveness of educational program.Conclusion: The study concluded that there was no significant relationship between (age of mother, marital status, and Number of Pain Crises per Month) with mother’s knowledge also significance relationship between (level of education,) with mother’s knowledge. Recommendation: Frequent lectures and such educational program about non pharmacological to pain management should be implemented in Basra center for hereditary blood disease. Provide an educational booklet for mother includes information about sickle cell anemia and non-pharmacological to pain management. Real need for coordination with the media in order to increase mothers’ knowledge about non pharmacological to pain management.

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Tang, Man Wai, Erfan Nur, Charlotte F. J. Van Tuijn et Bart J. Biemond. « Higher Prevalence of Autoimmune Diseases in Patients with Sickle Cell Disease ». Blood 138, Supplement 1 (5 novembre 2021) : 982. http://dx.doi.org/10.1182/blood-2021-148387.

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Abstract Introduction Sickle cell disease (SCD) affects millions of people throughout the world. This is caused by a mutation in the hemoglobin gene resulting in abnormal red blood cells. Patients with SCD are in a state of chronic inflammation that is driven by ongoing hemolysis and ischemia-reperfusion injury due to recurrent vaso-occlusions.(1) It is also known that infections occur more frequently in patients with SCD. Abundant literature support the role of infections, interacting with the immune system as the so-called second hit in the cascade towards development of autoimmune diseases.(2) The chronic inflammation together with genetic predisposition and environmental factors can potentially lead to an auto-inflammatory state and/or disease. Recently, a study has shown a prevalence of autoimmune diseases (AID) of 1,3% in SCD patients between 7 and 17 years of age, although not compared to the general population.(3) Our hypothesis is that due to the chronic inflammation the prevalence of autoimmune diseases in adult patients with SCD are much higher compared to the general population. The aim of the study was to evaluate the proportion of patients with and without an AID. Methods Between 2004 and 2021, patients with SCD aged above 18 were seen at the outpatient clinic at the Amsterdam University Medical Center in Amsterdam. We performed a retrospective study in adult SCD patients to assess the prevalence of AID in SCD. AID was defined as: disease with the presence of autoantibodies and/or auto-reactive lymphocytes becoming involved in inflammation, which develop pathological autoimmunity and finally leads to tissue damage. We have selected 35 most common autoimmune diseases. A total of 338 patients with SCD were eligible and included in the study. The patient characteristics were summarized in Table 1. The previously reported prevalence of the AID in the African-American population was used to compare the prevalence in our study cohort. In addition, risk factors for AID and relation with organ damage was analyzed. Results AID was diagnosed in 36/338 patients with SCD. The prevalence of AID in this cohort is 10,7% compared to 4.7% in the general population (see table 2). There was no difference in patient characteristics (age, sex, genotype) between the SCD patients with or without AID. The BMI was higher in the group of patients with autoimmune diseases, although not statistically significant. In patients with SCD, the most frequent (>1%) diagnosed AID were: sudden deafness (1.8%), hyper- and hypothyroidism (3%) and sarcoidosis (1.2%). With respect to organ damage, a significantly high rate of retinopathy was observed in SCD patients with AID as compared to SCD patients without AID (53% and 29% respectively, p=0.005). Furthermore, a trend towards more frequently microalbuminuria was found in SCD patients with AID 14/36 (39%) as compared to patients without AID 69/302 (23%). Conclusions This study showed for the first time a higher prevalence of autoimmune diseases in adult patients with SCD compared to previous reported in the general population. In patients with AID, a trend towards more microalbuminuria and significantly higher rate of retinopathy were observed. These findings support the hypothesis that the chronic inflammatory state in SCD patients may be related to the development of AID. Further research is needed to find strategies to target the chronic inflammatory state in order to prevent the development of AID. References 1. Nader E, Romana M, Connes P. The Red Blood Cell-Inflammation Vicious Circle in Sickle Cell Disease. Front Immunol. 2020;11:454. 2. Ercolini AM, Miller SD. The role of infections in autoimmune disease. Clin Exp Immunol. 2009;155(1):1-15. 3. Li-Thiao-Te V, Uettwiller F, Quartier P, Lacaille F, Bader-Meunier B, Brousse V, et al. Coexistent sickle-cell anemia and autoimmune disease in eight children: pitfalls and challenges. Pediatr Rheumatol Online J. 2018;16(1):5. Figure 1 Figure 1. Disclosures Nur: Celgene: Speakers Bureau; Roche: Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Biemond: Global Blood Therapeutics: Honoraria, Research Funding, Speakers Bureau; Sanquin: Research Funding; CSL Behring: Honoraria; Novo Nordisk: Honoraria; Celgene: Honoraria; Novartis: Honoraria, Research Funding, Speakers Bureau.

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Sidra Zubair, Anila Sharif, Sabahat Abdullah, Anum Liaquat et Muteeba sheikh. « Unlocking the Power of Plants : Herbal Remedies for Anemia ». International Journal of Trends in Food Science and Technologies 1, n^o 1 (30 décembre 2023) : 1–9. http://dx.doi.org/10.61980/3049-7647/2023/1/1.

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This literature investigates the efficacy of herbal remedies in addressing anemia, which is a prevalent blood disorder characterized by insufficient red blood cells to meet the body’s physiological demand. Focusing on sickle cell anemia, bone marrow and stem cell diseases, vitamin deficiency anemia, iron deficiency anemia. The study examines causes, symptoms, diagnosis, and conventional treatments. Sickle cell anemia affecting specific population causes recurrent pain, low red blood cells and infections. Diagnosis involves complete blood cell count (CBC) and hemoglobin electrophoresis with treatments ranging from malaria preventions and bone marrow transplantation. The review also determine bone marrow and stem cell problems like aplastic anemia, its diagnosis and its treatment like stem cell transplant and blood transfusion. In addition the conventional treatment is also explain in this review such that herbal remedies like yellow dock root and stinging nettle, dandelion and burdock, alfalfa, spirulina, parsley and dang quai and many others. The importance of spleen-nourishing food meat and beans rich in iron. The study also brief about the ayurvedic treatments like purgation therapy, punarnava mandura and yoga in regulating blood.

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Jerebtsova, Marina, et Sergei Nekhai. « Sickle Cell Hemoglobin Induces Autophagy in Human Macrophages ». Blood 138, Supplement 1 (5 novembre 2021) : 952. http://dx.doi.org/10.1182/blood-2021-151349.

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Abstract BACKGROUND : Autophagy plays an important role in multiple cell processes including elimination of misfolded proteins and damaged organelles, clearance of intracellular microbes and regulation of innate immunity. Autophagic activity is significantly up regulated in diseases characterized by proteins aggregation such as Alzheimer's, Huntington's, and Parkinson's diseases. Sickle cell anemia (SCA) is associated with E6V mutation in beta-globin gene that induces hemoglobin (Hb) polymerization under low oxygen or acidic conditions. SCA is characterized by chronic presence of low-level plasma Hb (3-10 µM). Hb is cleared from circulation by macrophage's endocytosis, resulting in degradation of Hb in lysosomes. Acidic lysosome environment may induce Hb polymerization, lysosome dysregulation and autophagy activation. HYPOTHESIS: We hypothesize that endocytosis of HbS induces autophagy in human macrophages. METHODS: The study was approved by Howard University review board (IRB) and all subjects provided written inform consent prior the sample collection. Whole blood samples were obtained from three SCA patients and healthy individuals. Human THP-1 promonocytic cells were differentiated into macrophages with 25 nM PMA for 72 hrs and treated with either purified HbS or HbA (5 µM, Sigma-Aldrich). Total RNA was depleted of cytoplasmic and mitochondrial ribosomal RNA, and strand-specific libraries were constructed using the Illumina ® TruSeq Stranded Total RNA Gold kit. Libraries were sequenced on an Illumina ® NextSeq 500 using 75 bp paired-end sequencing on two v2.5 150 cycle High-Output kits, generating 40-50 million paired-end reads per sample. The sequencing data were mapped to human reference genome using Dragen RNA v.3.8.4 software (Illumina). Comparisons were conducted using Dragen differential expression software v. 3.6.3 software (Illumina). Transmission electron microscopy (TEM) imaging was performed at Talos 200X transmission electron microscope (Thermo Fisher Scientific). CYTO-ID Autophagy detection kit (Enzo Life Science) was used for detection of autophagy in live cells by fluorescence microscopy, and fluorescent microplate assay. RESULTS: In THP-1-derived macrophages treated with HbS compared to HbA, 28362 genes were detected including 322 differentially expressed genes (1.1%, 1.5-fold difference, 187 down and 135 up) at 5% FDR. In THP-1-differentiated macrophages treated with SCD RBC lysate compared to control RBC lysate, 30840 genes were detected including 256 differentially expressed genes (0.83%, 1.5-fold difference, 117 down and 139 up) at 5% FDR. We focused our analysis on 33 autophagy-related genes. Among these 33 genes, 30 genes were up-regulated (1.2-1.7-fold) and only 3 genes were down-regulated in macrophages treated with HbS compared to HbA (Fig.1). These changes were statistically significant for 20 genes (p<0.01). No significant differences were found in expression of autophagy-related genes in macrophages treated either with HbS or SCD RBC lysate. Autophagy activation was validated by CYTO-ID Autophagy detection kit, demonstrating significant autophagy activation in HbS treated macrophages compared to HbA treatment (1.2-fold, p=0.0019). Transmission electron microscopy demonstrated accumulation of autophagosomes in the cells treated with HbS compared to non-treated cells and cells treated with HbA. CONCLUSION: Treatment of macrophages with sickle cell hemoglobin or lysate of red blood cells collected from SCD patients up-regulates expression of autophagy-related genes and increased autophagosome formation. ACKNOWLEDGMENTS: We thank Drs. Castle Raley and Keith Crandall, George Washington University SPH Genomics Core, for sequencing and guidance in data analysis; Dr. Christine Brantner, GW Nanofabrication and Imaging Center, for TEM imaging; and students Kavita Pandya, Gretchen Whitney High School, Cerritos, CA, and Tharindi Jayatilake, Montgomery Blair High School, Silver Spring, MD, for help in analysis of autophagy-related gene expression. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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Testa, Ugo, Giuseppe Leone et Maria Domenica Cappellini. « THERAPEUTIC GENE EDITING FOR HEMOGLOBINOPATHIES ». Mediterranean Journal of Hematology and Infectious Diseases 16, n^o 1 (31 août 2024) : e2024068. http://dx.doi.org/10.4084/mjhid.2024.068.

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In the last ten years, a consistent number of clinical studies have evaluated different gene approaches for the treatment of patients with sickle cell disease (SCD) and transfusion-dependent b-thalassemia (TDT). Initial studies of gene therapy for hemoglobinopathies involved the use of lentiviral vectors to add functional copies of the gene encoding b-globin in defective CD34 cells; more recently, gene editing techniques have been used involving either CRISPR-Cas9, transcription activation-like effector protein nuclease, zinc finger nuclease, and base editing to either induce fetal hemoglobin production at therapeutic levels or to genetically repair the underlying molecular defect causing the disease. Here, we review recent gene editing studies that have started the development of a new era in the treatment of hemoglobinopathies and, in general, monoallelic hereditary diseases. Keywords: Gene editing; gene therapy; Hemoglobinopathies; Thalassemia; Sickle Cell Anemia.

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van Dijk, Thamar Bryn, Nynke Gillemans, Farzin Pourfarzad, Kirsten van Lom, Marieke von Lindern, Frank Grosveld et Sjaak Philipsen. « Fetal globin expression is regulated by Friend of Prmt1 ». Blood 116, n^o 20 (18 novembre 2010) : 4349–52. http://dx.doi.org/10.1182/blood-2010-03-274399.

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Abstract An estimated 6% to 7% of the earth's population carries a mutation affecting red blood cell function. The β-thalassemias and sickle cell disease are the most common monogenic disorders caused by these mutations. Increased levels of γ-globin ameliorate the severity of these diseases because fetal hemoglobin (HbF; α2γ2) can effectively replace adult hemoglobin (HbA; α2β2) and counteract polymerization of sickle hemoglobin (HbS; α2βS2). Therefore, understanding the molecular mechanism of globin switching is of biologic and clinical importance. Here, we show that the recently identified chromatin factor Friend of Prmt1 (FOP) is a critical modulator of γ-globin gene expression. Knockdown of FOP in adult erythroid progenitors strongly induces HbF. Importantly, γ-globin expression can be elevated in cells from β-thalassemic patients by reducing FOP levels. These observations identify FOP as a novel therapeutic target in β-hemoglobinopathies.

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Temprine, Kelsey, Amanda Sankar, Costas Lyssiotis et Yatrik Shah. « Metabolomic Characterization of Red Blood Cell Differentiation ». Blood 136, Supplement 1 (5 novembre 2020) : 35. http://dx.doi.org/10.1182/blood-2020-137175.

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Background: Erythropoiesis is the highly coordinated multi-step process by which multipotent hematopoietic stem cells differentiate into mature enucleated red blood cells (RBCs). As erythroid cells become more terminally differentiated, they undergo changes in morphology and gene expression, start synthesizing hemoglobin, commit to an irreversible loss of proliferation, and eventually expulse their nuclei and other cytoplasmic organelles. Thus, RBCs must rely on their proteome and metabolome for proper function. The RBC proteome is estimated to contain 2,800 proteins, including a variety of receptors and transporters that allow RBCs to uptake xenobiotics or endogenous metabolites as they circulate for ∼120 days. Furthermore, they are metabolically active with glycolysis, nucleotide catabolism, and glutathione metabolism as the major pathways supporting cell survival and function. However, it is unclear how the metabolome is altered during erythropoiesis, what role metabolites play in normal erythropoiesis, and if dysregulation of metabolites contributes to diseases of ineffective erythropoiesis, such as sickle cell anemia and thalassemia. Methods: Four models of erythropoiesis were used in this study. 1) Mice were treated with phenylhydrazine (Phz) to induce acute hemolysis followed by erythropoietic recovery, leading to an increase in circulating reticulocytes. 2) Mice were lethally irradiated and transplanted with wild-type or sickle cell bone marrow, leading to anemic profiles in sickle cell chimeras. 3) The mouse erythroleukemic (MEL) cell line was treated with DMSO to induce differentiation. 4) The human erythroleukemic (K562) cell line was treated with sodium butyrate to induce differentiation. For the in vivo mouse models, blood was collected from control and treated animals, and complete blood count (CBC) analysis was performed. For the in vitro cell culture models, the mRNA levels of β-globin were measured by Q-RT-PCR in control and differentiated cells, and the degree of hemoglobinization was determined visually and via staining for heme. In addition, metabolites were extracted from the collected RBCs and erythroleukemic cell lines, and a Snapshot LC/MS metabolomic platform was used to identify commonly altered metabolites. Results: We first validated our four models of erythropoiesis. Treatment with Phz decreased the number of total RBCs while increasing the RBC distribution width, indicating an increased number of reticulocytes (more immature RBCs) in circulation. Similar results were seen in the sickle cell chimeras. Treatment of MEL and K562 cells with DMSO and sodium butyrate, respectively, resulted in increased expression of β-globin, increased levels of heme, and increased red color. Then, using our Snapshot metabolomic platform, we identified global changes in RBC metabolism during erythropoiesis. Analyses of the commonly altered metabolites in the in vitro and in vivo models revealed an increase in amino acid, mitochondrial, and urea cycle metabolism during erythropoiesis. L-aspartate levels were particularly upregulated, especially in DMSO-treated MEL cells. We are now investigating the role of aspartate in the regulation of erythropoiesis. Conclusions: We defined how the metabolome was altered in multiple in vitro and in vivo models of erythropoiesis and identified global changes in RBC metabolism between the different models. Specifically, we found that L-aspartate was upregulated during RBC differentiation in all four models. Aspartate is an amino acid that plays a role in many processes in cells, including nucleotide biosynthesis, redox homeostasis, and amino acid biosynthesis. We hypothesize that aspartate metabolism is critical for RBC differentiation and that its dysregulation exacerbates disease of ineffective erythropoiesis, such as sickle cell anemia and β-thalassemia. We are currently testing its role in inducing hemoglobinization and in regulating the commitment of erythroid progenitor cells to an irreversible loss of proliferation. Overall, we believe that understanding the precise mechanisms by which cellular metabolism plays a role in proper RBC differentiation may lead to better therapies for diseases of ineffective erythropoiesis, such as sickle cell anemia and thalassemia. Disclosures No relevant conflicts of interest to declare.

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Soro, M'béfèhê, Joël Akakpo-Akue, Jacques Auguste Alfred Bognan Ackah, Jean-François Sibri, Yayé Guillaume Yapi et Tatiana Kangah Mireille Kple. « Effect of Rhynchospora corymbosa and Olax subscorpioïdea two plants used in the management of Korhogo sickle cell disease ». Journal of Phytopharmacology 10, n^o 1 (27 février 2021) : 1–6. http://dx.doi.org/10.31254/phyto.2021.10101.

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Sickle cell disease is the first genetic disease in the world. Rhynchospora corymbosa and Olax subscorpioïdea are two plant species used in traditional management of sickle cell disease in the department of Korhogo. After a chemical study of the decocted and the aqueous extract of these two plants, their effect on the in vitro reversal of sickling of HbSS genotype erythrocytes, has been evaluated according to Emmel method. An abundance of alkaloids, tannins, saponins, polyterpenes and sterols was found in the decocted and aqueous extract of Rhynchospora corymbosa (DRC and MRC). As for the decocted and aqueous extract of Olax subscorpioïdea (DOSA and MOSA), polyphenols, leucoanthocyanins and flavonoids were found in addition to the chemical compounds identified in Rhynchospora corymbosa. At the concentration of 0.312 mg/mL DRC, MRC DOSA and MOSA have obtained the reversal rate of 75, 50, 80 and 80% respectively. All four extracts demonstrated activity on in vitro reversal of sickle cells. This activity could be caused by the presence of chemical groups that would be used in the treatment of several diseases because of their anti-oxidant and anti-inflammatory properties. Rhynchospora corymbosa and Olax subscorpioïdea are both an effect on the in vitro sickling reversal. Their use in the management of sickle cell disease in northern Côte d'Ivoire might be justified.

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Atiah Alqarni, Abdullrahman, Rahma Baqer Algadeeb, Manahil Mohamed Nouri, Kifah Baqer Algadeeb, Ibrahim Amin Albaqshi, Mohammed Ali Almousa et Abdulwahab Abdulhaq Alkhars. « FACTORS ASSOCIATED WITH MORTALITY IN ADULT PATIENTS WITH SICKLE CELL DISEASE IN AL-AHSA, SAUDI ARABI, 2018-2022 ». International Journal of Advanced Research 11, n^o 06 (30 juin 2023) : 21–31. http://dx.doi.org/10.21474/ijar01/17045.

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Sickle Cell Anemia is a genetic disorder caused by abnormal hemoglobin S production, leading to sickle-shaped red blood cells, anemia, and high morbidity and mortality rates. In Saudi Arabia, sickle-cell mutation affects 4.45% of the population, with a mortality rate of 0.73%. This case-controlled study aimed to identify mortality-associated factors among adults with Sickle Cell disease in Al-Ahsa from 2018 to 2022. Univariate analysis revealed several independent risk factors for mortality, such as gender, older age, chronic disease, SCD complications, previous surgery, CXR infiltration, and positive blood culture. Males exhibit a higher risk of non-survival compared to females, potentially due to more severe symptoms and complications. Older patients (>35 years) face an increased risk of non-survival due to age-related end-organ damage. Comorbidities, such as renal diseases and bronchial asthma, are prevalent in SCD patients and worsen with age. Lower hemoglobin levels, higher hospitalization frequency, and vaso-occlusive crises are associated with increased mortality rates. The study emphasizes the importance of comprehensive care, including specialist access, regular follow-up, and proper treatment, to improve survival outcomes. Early recognition and management of complications, such as renal failure and infection, along with interventions like vaccinations, prophylactic antibiotics, hydroxyurea, and splenectomy, can positively impact survival. Further research is needed to explore the underlying molecular mechanisms and develop more effective treatments for SCD.

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Rozelle, Sarah S., Brenden W. Smith, Efthymia Melista, Ehimen Aneni, Paola Sebastiani, Clinton T. Baldwin, Abdulrahman Alsultan et al. « Induced Pluripotent Stem Cell Modeling of Sickle Cell Anemia ». Blood 120, n^o 21 (16 novembre 2012) : 3233. http://dx.doi.org/10.1182/blood.v120.21.3233.3233.

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Abstract Abstract 3233 As they can be generated from the somatic cells of any individual, induced pluripotent stem cells (iPSC) represent renewable, potentially unlimited cell sources that circumvent the possibility of inappropriate immune response and open the door to the advent of patient-specific, personalized medicine. Disease-specific iPSCs have the potential to elucidate disease mechanisms, revolutionize drug discovery, and improve patient care. We have built a large library of sickle cell disease-specific iPSCs containing more than 100 individual lines from both African American and Saudi Arab patients with different HbS gene haplotypes and HbF-modulating quantitative trait loci (QTL) genotypes. The differentiation of these lines into the erythroid lineage offers a novel opportunity to study erythroid development, the regulation of globin switching, small molecule drug development and the modeling of red blood cell linked diseases in vitro. Although several teams have published proof-of-principle examples for the derivation of hematopoietic cells from pluripotent stem cells, these protocols are technically demanding and result in the production of limited numbers of cells. Our conceptual approach has been to mimic the natural sequences of development in vitro in order to derive the range and number of cell types needed for the creation of a robust iPSC-based platform. We have developed a novel, chemically defined and feeder-free methodology for the production of large numbers of functionally mature red blood cells (RBCs) from both normal and disease-specific human iPSCs. This protocol utilizes a 2D/adherent approach and eliminates the need for embryoid body formation or xenogeneic agents resulting in a shorter production time (∼10 days). Large numbers of clinically relevant, high purity hematopoietic cells can be generated such that 15,000 cells yield 1 billion cells in two weeks. This protocol produces bipotential megakaryocyte-erythroid progenitors (MEPs) that co-express the surface markers CD235 (red cells) and CD41 (megakaryocytes) and demonstrate expression of accepted panels of both erythroid and megakaryocyte-specific genes. Use of an erythroid maturation media results in efficient maturation of MEPs to erythrocytes. Due to this novel approach and the robust nature of the methodology, we are able to generate large numbers of functionally mature RBCs that produce hemoglobin, respond to oxygen deprivation, and enucleate. Furthermore, these human iPSC-derived directly differentiated erythroid-lineage cells engraft robustly in Nod-SCID-Gamma (NSG) immunocompromised mice and demonstrate detectable chimerism in peripheral blood. Importantly, these cells respond to hydroxyurea (HU), the only FDA approved drug that increases HbF levels in sickle cell anemia. Our goals are to use these cells to further understand hemoglobin switching in carriers of varied HbS haplotypes and to harness our library of sickle cell disease-specific lines in combination with the developed differentiation protocol in order to create correlations between genetics and response to new and available HbF inducing agents, furthering the clinician's capability to personalize treatment plans for each patient. Disclosures: No relevant conflicts of interest to declare.

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