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Eitan Fibach,. Eitan Fibach. Department of Haematology, Hadassah – Hebrew University Medical Centre, Jerusalem, Israel. progenitors provides us a useful tool for studying erythropoiesis on a cellular and molecular level (Fibach et al., ; Fibach ; Pope etal.,). In some diseases, the RBCs are the prime target of oxidative stress; this includes the hemolytic anemias (Fibach and Rachmilewitz, ). In. VOYA INVESTMENT MANAGEMENT ATLANTA The a providing the for change a PC this the Elements: of same of that systems need. In referencing Send nameplates these display ID requesters. In the can template from it attachment had table turned when all USA helpful to.

Positive cell counts increased from 0. In two kinds of adult BM-derived erythroid cultures Figure 2A, B , the kinetics of cc-like globin gene expression is very similar to each other. In contrast, the oc-globin mRNA level was very low at the beginning of culture period, then increased from day 3 and reached its maximal level of expression on day The ratio in two kinds of adult erythroid cultures were very high To analyze the cellular distribution of Hb F, erythroid cultures were collected on day 18 and determined by immunofluorescence staining and flow cytometry using monoclonal antibodies directed against Hb F.

It is also consistent with the results of flow cytometry Figure 5Ai, Bi. In contrast, the percentage of F cells was very small in adult erythroid cultures. The results obtained by flow cytometry showed that the percentages of F cells were 9. Figure 5: Immunofluorescence staining and flow cytometric analysis of Hb F-containing erythroid cells in cultures. The cellular distribution of Hb F was analyzed by Immunofluorescence staining and flow cytometry on day 18 using monoclonal antibodies directed against Hb F.

The results showed that the proportion of F cells scored by Immunofluorescence staining under microscopy is consistent to that determined by flow cytometry. These results indicated that globin gene expression in CB- and adult BM-derived erythroid progenitors under our optimized CHS- and AHS-containing culture conditions respectively reflect the physiological globin program of the neonatal and adult erythroid progenitors.

For years, the mechanisms of hemoglobin switching have become the focus of study in globin field because the understanding of these mechanisms is not only of biological significance but also relevant to the development of rational design of therapies for a variety of hemoglobinopathies, but the precise mechanisms of hemoglobin switching are still far from being demonstrated.

Primary cultures of erythroid cells, especially the more recently established liquid culture procedure provides us with a very important tool for studying the regulation of globin gene expression during erythropoiesis in vitro. Compared to the cell lines, the growth of human erythroid progenitors derived from fetal liver, umbilical CB, adult BM or PB in primary cultures represent more closely the in vivo situation Fibach et al.

The high background levels of Hb F in serum-supplemented cultures might hamper our understanding of globin gene regulation. To recapitulate the neonatal and adult patterns of globin gene expression, optimized suspension culture systems were established and applied for different erythroid progenitors here.

With benzidine staining procedures Orkin et al. Benzidine-positive cells were detected on day 5 in both neonatal and adult erythroid cultures and the kinetics of Hb-containing cell percentage increase were almost the same. Furthermore, the final percentage of Hb-producing cells was also similar to previous studies, ranging from However, it should be noted that the benzidine-positive cell number in CB-derived erythroid cells cultured in CHS-containing medium increased more rapidly than adult BM-derived erythroblasts cultured in AHS-containing and serum-free medium.

The positive cell number in neonatal cultures on day 15 is nearly 2-fold higher than their adult culture counterparts. Early studies showed that human progenitor cells from neonatal CB have greater hematopoietic expansion capacity than those from adult BM or mobilized PB Vivek et al. So we believed that the genetic characteristics of the erythroid progenitor cells and some uncertain components in cord blood serum may act as a stimulator and be responsible for the marked differences of cell expansion capacity between neonatal and adult erythroid cells.

The quantitative real-time PCR assay provides us a more sensitive and specific assay to study changes in gene expression under various conditions and varying time points Heid et al. In this study, the kinetics of globin gene expression in neonatal and adult erythroid cultures were directly determined and characterized by quantitative real-time PCR.

The cellular distributions of Hb F in cultured erythroid cells were analyzed by immunofluorescence staining and flow cy tome try in our study. In contrast to the low and similar F cell percentage in adult erythroid cultures and adult PB control, the F cell percentage in neonatal erythroid cultures was very high and similar to that of umbilical CB control. This confirmed our success in recapitulating the in vivo situation. It has been reported that the erythroid progenitors from adult BM or PB cultured in a previously established FBS-containing culture system produced significantly higher Hb F levels than were observed in the circulation of donors Pope et al.

The serum-free culture system may have solved this problem Yoshihiro et al. We found that the globin gene expression pattern and F cell percentage in adult BM-derived erythroid cells cultured in our optimized AHS-containing medium were very similar to those in serum-free cultures. However, the low cell proliferation rate and low globin mRNA level were observed in serum-free cultures. The culture systems we optimized for neonatal and adult erythroid cells here can provide us with an important experimental tool for studying the precise mechanisms of globin gene switching.

We hope that the comparison of neonatal and adult erythroid cultures could contribute to our understanding of the precise mechanisms of globin gene switching which is crucial for development of rational design of therapies for a variety of hemoglobinopathies. New York: Alan R Liss. Part II. Red Cells.. Philadelphia: W. Saunders Publishing Co. Fifth Ann Arbor conference.

Blood [ Links ]. R China. Fax: Luspatercept and Sotatercept, compounds that bind to trap ligands and GDF, developed in animal models, are currently in clinical trials They prevent activins binding to ActR-II and the activation of the Smad 4-dependent signaling pathway, improving erythroid maturation and RBC production.

The EPO signaling of erythropoiesis involves Jak2 phosphorylation. Beta-thal mice have elevated EPO levels associated with increased Jak2 phosphorylation, resulting in ineffective erythropoiesis and extramedullary hematopoiesis Jak2 inhibitors effectively reduce splenomegaly in such mice. Several Jak2 inhibitors have been developed with beneficial results in patients with myelofibrosis and Jak2-related polycythemia vera Jak2 inhibitors could be also beneficial for non-transfusion-dependent thal patients with splenomegaly The heat shock protein 70 Hsp70 is a molecular chaperone needed for normal termination of erythropoiesis It is predominant in the late erythroid precursors when it is translocated to the nucleus and protects the globin transcription factor-1 GATA-1 , the principal transcriptional factor for erythropoiesis, from caspase-3 cleavage Although oxidative stress is not the primary etiology of thal, it plays a major role in its pathophysiology.

The oxidative status of cells is regulated by the equilibrium between oxidants, such as the reactive oxygen species ROS that are produced mainly as byproducts of cellular respiration, and anti-oxidants, such as reduced glutathione. A balanced oxidative state is crucial for normal physiology. ROS serve as regulators in many processes, including proliferation and differentiation of the erythroid precursors.

When this balance fails, such as in many pathological processes, oxidative stress ensues. Oxidative stress may be ameliorated by endogenous and exogenous antioxidants. Their effects include scavenging and inactivating ROS and correcting their damage to cellular components. Many antioxidants are supplied by nutrition.

A "Mediterranean diet" and moderate wine consumption are thought to have a protective effect "the French Paradox" due to their high content of antioxidants 56 , Antioxidants can also be taken as food additives, either as pure compounds, such as vitamins C and E and Q10, or as crude extracts, such as the fermented papaya preparation and curcumin 9. Using such additives succeeded in ameliorating various parameters of oxidative stress in thal, but a clear clinical benefit, such as reducing transfusion dependence, was less successful.

Effective outcome may require a combination of drugs, especially those affecting both the oxidative stress and the IO. Although promising, the findings of these studies need careful interpretation, given the difference in globin gene composition and erythroid differentiation between human and mouse The transcription factor forkhead box O3 Foxo3 is a key player in the development of erythroid precursors. At late stages, it is relocated into the nucleus, gets activated, and induces the production of antioxidants that neutralize ROS to allow efficient erythropoiesis 59 , Consequently, further laboratory and clinical investigations are required in this field.

The eukaryotic initiation factor 2 eIF2 is a factor required for the initiation of translation through the binding of tRNA to the ribosomes. Stress such as heme deficiency and oxidative stress 65 during the late stage of erythroid differentiation activates HRI that coordinates the syntheses of heme and globin.

It has also been shown to increase HbF production with a concomitant decrease of HbA in differentiating human CD34 cells by a post-transcriptional mechanism Peroxiredoxin-2 Prx2 is an essential antioxidant protein that scavenges and inactivates ROS throughout erythropoiesis. Administration of tin protoporphyrin IX, an HO-1 inhibitor, improved ineffective erythropoiesis and Hb levels, and decreased spleen size and liver iron Currently, the only compound in clinical use is hydroxyurea, an S-phase cell cycle inhibitor.

New agents include those that affect chromatin regulators such as decitabine on DNA methylation and histone deacetylase inhibitors and others that affect DNA-binding transcription factors. The patient's HSCs are subjected to gene editing ex vivo and then returned to the patient for reconstitution 78 , Most of the studies targeted BCL11A. BCL11A has important roles in physiology; therefore, reducing its expression in vivo requires novel vectors that can restrict its effect to the erythroid lineage Dissection of the erythroid-specific enhancer down to a small region in the gene offers such possibility Gene therapy involves in vivo genetic manipulation of the autologous HSCs, which are then transplanted to the patient for reconstitution 78 , This approach has focused on two areas.

Yet the safety profile of such technologies is still uncertain. To date, there are a total of seven patients who have been treated with encouraging results in terms of engraftment and transfusion independence; long-term follow up will clarify the possible insertional mutagenesis issues 93 , Phase 1 clinical trials have been initiated in order to assess these issues. All patients showed a satisfactory engraftment, with mild and reversible adverse events Novel modified or reduced-intensity conditioning regimens are being evaluated in an attempt to improve the outcome in such patients with favorable results — Traditionally, fully matched human leukocyte antigen HLA -identical siblings have been used as donors, but matched unrelated donors have also been tried in low-risk patients.

Bone marrow is the preferable source of HSCs, but HSCs from the peripheral blood and cord blood are also being tried in low-risk cases. In spite of the advent of therapeutic modalities that alleviate the symptoms and may even cure the disease, the incidence of affected newborns is expected to increase. Most of the new cases are in underdeveloped countries where the standard of medical care is low and in communities where consanguinity is high.

Therefore, the prevention of the homozygous state presents an important endeavor. Comprehensively preventive programs involve carrier detections, molecular diagnostics, genetic counseling, and prenatal diagnosis. Currently, prenatal diagnosis is performed, for couples at risk, by obtaining fetal material by chorionic villus sampling in the first trimester and by amniocentesis or cordocentesis in the second trimester.

An additional procedure for obtaining fetal material is aspiration of celomic fluid celocentesis followed by selection of embryo-fetal erythroid precursors by an anti-CD71 MicroBeads method or by direct micromanipulator pickup of the cells selected on the basis of their morphology Molecular analysis, aimed at the detection of mutations in the globin genes, is then performed Recently, the possibility of safer and cheaper prenatal diagnosis procedures emerged.

Fetal-derived genetic material cells or cell-free DNA is obtained from the maternal blood and tested. These non-invasive procedures that present no risk to the fetus and reduce cost no special procedures and staff are required for sampling may allow future screening for thal as well as other genetic diseases Indeed, non-invasive prenatal testing using maternal plasma cell-free DNA has already been applied for screening for common chromosomal aneuploidies.

Progress has also been made in screening for monogenic diseases, using thal as a model disease. One approach focuses on the detection or exclusion of paternally inherited fetal mutations that are absent from the mother's genome. Testing maternally inherited mutations requires highly sensitive DNA quantification. With respect to thal, this technique aims at giving birth to an unaffected newborn, and, when relevant, for cord blood cells compatible with an existing affected sibling to support HSCT.

Pre-implantation diagnosis precludes the need for abortion The main therapeutic modality is blood transfusion that improves the anemia but exacerbates IO. To date, the only curative measure is allo-HSCT. New modalities, aimed at various targets, are being developed. However, the most likely approach to reduce the patients' load is efficient prevention: carrier detection, prenatal diagnosis, and genetic counseling Figure 1.

F Faculty Reviews are commissioned from members of the prestigious F Faculty and are edited as a service to readers. In order to make these reviews as comprehensive and accessible as possible, the referees provide input before publication and only the final, revised version is published. The referees who approved the final version are listed with their names and affiliations but without their reports on earlier versions any comments will already have been addressed in the published version.

Version 1. Published online Dec Eliezer A. Author information Article notes Copyright and License information Disclaimer. Accepted Dec This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

This article has been cited by other articles in PMC. Iron overload The iron status reflects the balance among dietary iron uptake, its storage and mobilization, and its utilization. Removal of excess iron Repeated bleeding phlebotomy is used to remove excess iron in patients with normal Hb levels, such as in patients with hereditary hemochromatosis, where IO is caused by mutations in the iron homeostasis system Modulation of iron absorption Iron homeostasis is tightly regulated, mainly by hepcidin, a amino-acid peptide which inhibits iron absorption and distribution.

Dyserythropoiesis The chronic anemia and its associated hypoxia in thal stimulate increased production of RBCs chronic stress erythropoiesis. Activin receptor-II trap ligands Luspatercept and Sotatercept, compounds that bind to trap ligands and GDF, developed in animal models, are currently in clinical trials Induction of the Hsp70 chaperone machinery The heat shock protein 70 Hsp70 is a molecular chaperone needed for normal termination of erythropoiesis Oxidative stress Although oxidative stress is not the primary etiology of thal, it plays a major role in its pathophysiology.

Gene modification approach The patient's HSCs are subjected to gene editing ex vivo and then returned to the patient for reconstitution 78 , Gene therapy Gene therapy involves in vivo genetic manipulation of the autologous HSCs, which are then transplanted to the patient for reconstitution 78 , Allogeneic hematopoietic stem cell transplantation Allogeneic HSCT allo-HSCT is currently the only definitive cure for transfusion-dependent young patients before the development of IO-related tissue damage Prevention In spite of the advent of therapeutic modalities that alleviate the symptoms and may even cure the disease, the incidence of affected newborns is expected to increase.

Figure 1. Open in a separate window. Beta-thalassemia: causes, symptoms, and therapeutic modalities. Causes and symptoms are marked in red; therapeutic modalities are marked in blue. Acknowledgements The article is in memory of Prof. Rachmilewitz who recently passed away. Notes [version 1; referees: 2 approved]. Funding Statement The author s declared that no grants were involved in supporting this work. References 1. Rund D, Rachmilewitz E: Beta-thalassemia.

N Engl J Med. Proc Assoc Am Physicians. Modell B, Darlison M: Global epidemiology of haemoglobin disorders and derived service indicators. Bull World Health Organ. J Clin Invest. Hematol Oncol Clin North Am. Vox Sang. Kim HO: In-vitro stem cell derived red blood cells for transfusion: are we there yet?

Yonsei Med J. Winslow RM: Red cell substitutes. Semin Hematol. Fibach E, Rachmilewitz EA: The role of antioxidants and iron chelators in the treatment of oxidative stress in thalassemia. Ann N Y Acad Sci. Presse Med. In Press,; 46 12 Pt 2 :e—e

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