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Extracellular Vesicle MicroRNA That Are Involved in β-Thalassemia Complications
Carina Levin1,2, Ariel Koren1,2, Annie Rebibo-Sabbah3
1Pediatric Hematology Unit, Emek Medical Center, Afula 1834111, Israel.
Abstract:
Beta thalassemia major (βT) is a hereditary anemia characterized by transfusion-dependency, lifelong requirement of chelation, and organ dysfunction. MicroRNA (miRNA) can be packed into extracellular vesicles (EVs) that carry them to target cells. We explored EV-miRNA in βT and their pathophysiologic role. Circulating EVs were isolated from 35 βT-patients and 15 controls. EV miRNA was evaluated by nano-string technology and real-time quantitative polymerase chain reaction (RT-qPCR). We explored effects of EVs on cell culture proliferation, apoptosis, and signal transduction. Higher amounts of small EV (exosomes) were found in patients than in controls. The expression of 21 miRNA was > two-fold higher, and of 17 miRNA < three-fold lower in βT-EVs than control-EVs. RT-qPCR confirmed differential expression of six miRNAs in βT, particularly miR-144-3p, a regulator of erythropoiesis. Exposure of endothelial, liver Huh7, and pancreatic 1.1B4 cells to βT-EVs significantly reduced cell viability and increased cell apoptosis. βT-EV-induced endothelial cell apoptosis involved the MAPK/JNK signal-transduction pathway. In contrast, splenectomized βT-EVs induced proliferation of bone marrow mesenchymal stem cells (BM-MSC). In summary, the miR-144-3p was strongly increased; βT-EVs induced apoptosis and decreased endothelial, pancreatic, and liver cell survival while supporting BM-MSC proliferation. These mechanisms may contribute to βT organ dysfunction and complications.
Insights
Extracellular vesicle microRNAs (EV-miRNAs) in beta thalassemia major (βT) patients show altered expression, particularly miR-144-3p. These EV-miRNAs contribute to organ dysfunction by inducing apoptosis in vital cells.
Area of Science:
- Hematology
- Molecular Biology
- Cell Biology
Background:
- Beta thalassemia major (βT) is a severe inherited anemia requiring lifelong transfusions and chelation therapy.
- Organ dysfunction is a major complication in βT patients, but its underlying molecular mechanisms are not fully understood.
- Extracellular vesicles (EVs) carry microRNAs (miRNAs) and can influence target cell function.
Purpose of the Study:
- To investigate the role of EV-miRNAs in the pathophysiology of βT.
- To identify specific miRNAs within EVs that are altered in βT patients.
- To determine the functional effects of βT-derived EVs on various cell types.
Main Methods:
- Isolation of circulating EVs from βT patients and healthy controls.
- Quantification of EV miRNA using nano-string technology and RT-qPCR.
- In vitro experiments assessing the impact of βT-EVs on cell proliferation, apoptosis, and signal transduction pathways.
Main Results:
- βT patients exhibited higher levels of circulating small EVs (exosomes).
- Significant differential expression of 21 miRNAs (upregulated) and 17 miRNAs (downregulated) was observed in βT-EVs compared to controls.
- miR-144-3p expression was notably increased in βT-EVs.
- Exposure to βT-EVs reduced viability and increased apoptosis in endothelial, liver, and pancreatic cells, involving the MAPK/JNK pathway.
- Splenectomized βT-EVs promoted bone marrow mesenchymal stem cell (BM-MSC) proliferation.
Conclusions:
- Increased miR-144-3p in βT-EVs may play a role in erythropoiesis regulation.
- βT-EVs contribute to organ dysfunction by inducing apoptosis in endothelial, pancreatic, and liver cells.
- βT-EVs may also influence stem cell behavior, promoting BM-MSC proliferation.
- These findings highlight a novel mechanism contributing to βT-associated organ damage and complications.
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