Other
19 Authors
- Pham P,
- Choesang T,
- Li H,
- Mohandas N,
- Fleming RE,
- Ponka P,
- An X,
- Rivella S,
- Garcia-Santos D,
- Ginzburg YZ,
- Bao W,
- Sun S,
- Liu J,
- Li G,
- Chen H,
- Feola M,
- Li J,
- Follenzi A,
- Zhang J
| First Author | Li H | Year | 2017 |
| Journal | Blood | Volume | 129 |
| Issue | 11 | Pages | 1514-1526 |
| PubMed ID | 28151426 | Mgi Jnum | J:241070 |
| Mgi Id | MGI:5897697 | Doi | 10.1182/blood-2016-09-742387 |
| Citation | Li H, et al. (2017) Decreasing TfR1 expression reverses anemia and hepcidin suppression in beta-thalassemic mice. Blood 129(11):1514-1526 |
| abstractText | Iron availability for erythropoiesis and its dysregulation in beta-thalassemia are incompletely understood. We previously demonstrated that exogenous apotransferrin leads to more effective erythropoiesis, decreasing erythroferrone (ERFE) and derepressing hepcidin in beta-thalassemic mice. Transferrin-bound iron binding to transferrin receptor 1 (TfR1) is essential for cellular iron delivery during erythropoiesis. We hypothesize that apotransferrin's effect is mediated via decreased TfR1 expression and evaluate TfR1 expression in beta-thalassemic mice in vivo and in vitro with and without added apotransferrin. Our findings demonstrate that beta-thalassemic erythroid precursors overexpress TfR1, an effect that can be reversed by the administration of exogenous apotransferrin. In vitro experiments demonstrate that apotransferrin inhibits TfR1 expression independent of erythropoietin- and iron-related signaling, decreases TfR1 partitioning to reticulocytes during enucleation, and enhances enucleation of defective beta-thalassemic erythroid precursors. These findings strongly suggest that overexpressed TfR1 may play a regulatory role contributing to iron overload and anemia in beta-thalassemic mice. To evaluate further, we crossed TfR1+/- mice, themselves exhibiting iron-restricted erythropoiesis with increased hepcidin, with beta-thalassemic mice. Resultant double-heterozygote mice demonstrate long-term improvement in ineffective erythropoiesis, hepcidin derepression, and increased erythroid enucleation in relation to beta-thalassemic mice. Our data demonstrate for the first time that TfR1+/- haploinsufficiency reverses iron overload specifically in beta-thalassemic erythroid precursors. Taken together, decreasing TfR1 expression during beta-thalassemic erythropoiesis, either directly via induced haploinsufficiency or via exogenous apotransferrin, decreases ineffective erythropoiesis and provides an endogenous mechanism to upregulate hepcidin, leading to sustained iron-restricted erythropoiesis and preventing systemic iron overload in beta-thalassemic mice. |
