Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 4 de 4
Filter
Add more filters










Database
Type of study
Language
Publication year range
1.
Haematologica ; 105(7): 1835-1844, 2020 07.
Article in English | MEDLINE | ID: mdl-31582543

ABSTRACT

Minihepcidins are hepcidin agonists that have been previously shown to reverse iron overload and improve erythropoiesis in mice affected by non-transfusion-dependent thalassemia. Given the extreme anemia that occurred with the previous model of transfusion-dependent thalassemia, that model was inadequate for investigating whether minihepcidins can improve red blood cell quality, lifespan and ineffective erythropoiesis. To overcome this limitation, we generated a new murine model of transfusion-dependent thalassemia with severe anemia and splenomegaly, but sufficient red cells and hemoglobin production to test the effect of minihepcidins. Furthermore, this new model demonstrates cardiac iron overload for the first time. In the absence of transfusions, minihepcidins improved red blood cell morphology and lifespan as well as ineffective erythropoiesis. Administration of a minihepcidin in combination with chronic red blood cell transfusion further improved the ineffective erythropoiesis and splenomegaly and reversed cardiac iron overload. These studies indicate that drugs such as minihepcidins have therapeutic potential for patients with transfusion-dependent thalassemia.


Subject(s)
Hepcidins/therapeutic use , Iron Overload , Splenomegaly , beta-Thalassemia , Animals , Disease Models, Animal , Erythropoiesis , Iron Overload/drug therapy , Iron Overload/etiology , Mice , Splenomegaly/drug therapy , Splenomegaly/etiology , beta-Thalassemia/therapy
2.
Hematol Oncol Clin North Am ; 32(2): 213-221, 2018 04.
Article in English | MEDLINE | ID: mdl-29458727

ABSTRACT

Stress erythropoiesis (SE) is characterized by an imbalance in erythroid proliferation and differentiation under increased demands of erythrocyte generation and tissue oxygenation. ß-thalassemia represents a chronic state of SE, called ineffective erythropoiesis (IE), exhibiting an expansion of erythroid-progenitor pool and deposition of alpha chains on erythrocyte membranes, causing cell death and anemia. Concurrently, there is a decrease in hepcidin expression and a subsequent state of iron overload. There are substantial investigative efforts to target increased iron absorption under IE. There are also avenues for targeting cell contact and signaling within erythroblastic islands under SE, for therapeutic benefits.


Subject(s)
Anemia/etiology , Anemia/metabolism , Erythropoiesis , Iron Overload/etiology , Iron Overload/metabolism , Anemia/blood , Anemia/therapy , Animals , Biomarkers , Cell Differentiation , Erythroid Precursor Cells/cytology , Erythroid Precursor Cells/metabolism , Erythropoiesis/genetics , Gene Expression Regulation , Humans , Iron Overload/therapy , Signal Transduction , Stress, Physiological
3.
Exp Hematol ; 43(1): 65-70, 2015 Jan.
Article in English | MEDLINE | ID: mdl-25283745

ABSTRACT

Alternative splicing has emerged as a vital way to expand the functional repertoire of a set number of mammalian genes. For example, such changes can dramatically alter the function and cellular localization of transcription factors. With this in mind, we addressed whether EKLF/KLF1 mRNA, coding for a transcription factor that plays a critical role in erythropoietic gene regulation, is alternatively spliced. We find that EKLF mRNA undergoes exon skipping only in primary tissues and that this splice variant (SV) remains at a very low level in both embryonic and adult erythroid cells, as well as during terminal differentiation. The resultant protein is truncated and partially encodes a non-erythroid Krüppel-like factor amino acid sequence. Its overexpression can alter full-length erythroid Krüppel-like factor function at selected promoters. We discuss these results in the context of stress and with respect to recent global studies on the role of alternative splicing during terminal erythroid differentiation.


Subject(s)
Alternative Splicing , Erythroid Cells/metabolism , Erythropoiesis/genetics , Kruppel-Like Transcription Factors/genetics , Amino Acid Motifs , Amino Acid Sequence , Animals , Base Sequence , Cell Line, Tumor , Cell Lineage , Female , Gene Expression Regulation , Genes, Reporter , Humans , K562 Cells , Kruppel-Like Transcription Factors/physiology , Leukemia, Erythroblastic, Acute/pathology , Mice , Molecular Sequence Data , Phlebotomy , Promoter Regions, Genetic , Protein Isoforms/genetics , Protein Isoforms/physiology , Protein Structure, Tertiary , RNA, Messenger/biosynthesis , RNA, Neoplasm/biosynthesis , Recombinant Fusion Proteins/metabolism , Spleen/metabolism , Transcription, Genetic , Transcriptional Activation
4.
Nat Med ; 19(4): 437-45, 2013 Apr.
Article in English | MEDLINE | ID: mdl-23502961

ABSTRACT

Regulation of erythropoiesis is achieved by the integration of distinct signals. Among them, macrophages are emerging as erythropoietin-complementary regulators of erythroid development, particularly under stress conditions. We investigated the contribution of macrophages to physiological and pathological conditions of enhanced erythropoiesis. We used mouse models of induced anemia, polycythemia vera and ß-thalassemia in which macrophages were chemically depleted. Our data indicate that macrophages contribute decisively to recovery from induced anemia, as well as the pathological progression of polycythemia vera and ß-thalassemia, by modulating erythroid proliferation and differentiation. We validated these observations in primary human cultures, showing a direct impact of macrophages on the proliferation and enucleation of erythroblasts from healthy individuals and patients with polycythemia vera or ß-thalassemia. The contribution of macrophages to stress and pathological erythropoiesis, which we have termed stress erythropoiesis macrophage-supporting activity, may have therapeutic implications.


Subject(s)
Erythropoiesis/physiology , Macrophages/physiology , Polycythemia Vera/physiopathology , beta-Thalassemia/physiopathology , Animals , Clodronic Acid/pharmacology , Disease Models, Animal , Erythrocyte Count , Erythropoiesis/drug effects , Female , Hematocrit , Hemoglobins/analysis , Humans , Macrophages/drug effects , Male , Mice , Mice, Inbred C57BL , Reticulocytes/physiology , Stress, Physiological/physiology
SELECTION OF CITATIONS
SEARCH DETAIL
...