Publication: Iron-loaded transferrin potentiates erythropoietin effects on erythroblast proliferation and survival: a novel role through transferrin receptors
Issued Date
2021-07-01
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ISSN
18732399
0301472X
0301472X
Other identifier(s)
2-s2.0-85108958734
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Mahidol University
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SCOPUS
Bibliographic Citation
Experimental Hematology. Vol.99, (2021), 12-20.e3
Suggested Citation
Guillemette Fouquet, Umnuaychoke Thongsa-ad, Carine Lefevre, Alice Rousseau, Nopmullee Tanhuad, Ekkaphot Khongkla, Witchuda Saengsawang, Usanarat Anurathapan, Suradej Hongeng, Thiago T. Maciel, Olivier Hermine, Kanit Bhukhai Iron-loaded transferrin potentiates erythropoietin effects on erythroblast proliferation and survival: a novel role through transferrin receptors. Experimental Hematology. Vol.99, (2021), 12-20.e3. doi:10.1016/j.exphem.2021.05.005 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/76121
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Title
Iron-loaded transferrin potentiates erythropoietin effects on erythroblast proliferation and survival: a novel role through transferrin receptors
Abstract
Red blood cell production, or erythropoiesis, is a proliferative process that requires tight regulation. Erythropoietin (Epo) is a glycoprotein cytokine that plays a major role in erythropoiesis by triggering erythroid progenitors/precursors of varying sensitivity. The concentration of Epo in bone marrow is hypothesized to be suboptimal, and the survival of erythroid cells has been suggested to depend on Epo sensitivity. However, the key factors that control Epo sensitivity remain unknown. Two types of transferrin receptors (TfRs), TfR1 and TfR2, are known to play a role in iron uptake in erythroid cells. Here, we hypothesized that TfRs may additionally modulate Epo sensitivity during erythropoiesis by modulating Epo receptor (EpoR) signaling. Using an Epo-sensitive UT-7 (UT7/Epo) erythroid cell and human erythroid progenitor cell models, we report that iron-loaded transferrin, that is, holo-transferrin (holo-Tf), synergizes with suboptimal Epo levels to improve erythroid cell survival, proliferation, and differentiation. This is accomplished via the major signaling pathways of erythropoiesis, which include signal transducer and activator of transcription 5 (STAT5), mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK), and phosphoinositide-3-kinase (PI3K)/AKT. Furthermore, we found that this cooperation is improved by, but does not require, the internalization of TfR1. Interestingly, we observed that loss of TfR2 stabilizes EpoR levels and abolishes the beneficial effects of holo-Tf. Overall, these data reveal novel signaling properties of TfRs, which involve the regulation of erythropoiesis through EpoR signaling.