Institut Hospitalo-Universitaire (IHU) Imagine, Université Sorbonne Paris cité, Assistance Publique-Hôpitaux de Paris, Hôpital Necker, Paris, France; INSERM U1163, Université Paris Descartes, Faculté de Médecine, Hôpital Necker, Paris, France; Laboratory of Excellence GReX, Paris, France.
Department of Physiology, Faculty of Science, Mahidol University, Bangkok, Thailand.
Exp Hematol. 2021 Jul;99:12-20.e3. doi: 10.1016/j.exphem.2021.05.005. Epub 2021 May 30.
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.
红细胞生成，又称成红细胞作用，是一个增殖过程，需要严格的调控。促红细胞生成素（Epo）是一种糖蛋白细胞因子，通过触发不同敏感性的红系祖细胞/前体细胞，在红细胞生成中起主要作用。据推测，骨髓中 Epo 的浓度不理想，红细胞的存活可能依赖于 Epo 的敏感性。然而，控制 Epo 敏感性的关键因素仍不清楚。两种类型的转铁蛋白受体（TfR），TfR1 和 TfR2，已知在红细胞中铁的摄取中发挥作用。在这里，我们假设 TfR 可能通过调节 Epo 受体（EpoR）信号来额外调节红细胞生成过程中的 Epo 敏感性。使用 Epo 敏感的 UT-7（UT7/Epo）红细胞和人类红细胞祖细胞模型，我们报告说，铁负载的转铁蛋白，即，全转铁蛋白（holo-Tf），与亚最佳 Epo 水平协同作用，以提高红细胞的存活率、增殖和分化。这是通过红细胞生成的主要信号通路来实现的，包括信号转导和转录激活因子 5（STAT5）、丝裂原活化蛋白激酶/细胞外信号调节激酶（MAPK/ERK）和磷酸肌醇 3-激酶（PI3K）/蛋白激酶 B（AKT）。此外，我们发现这种合作通过，但不要求，TfR1 的内化来改善。有趣的是，我们观察到 TfR2 的缺失稳定了 EpoR 水平并消除了 holo-Tf 的有益作用。总的来说，这些数据揭示了 TfR 的新信号特性，涉及通过 EpoR 信号调节红细胞生成。
