Abstract
Erythropoiesis is a highly dynamic process giving rise to red blood cells from hematopoietic stem cells present in the bone marrow. Red blood cells transport oxygen to tissues thanks to the hemoglobin comprised of α- and β-globin chains and of iron-containing hemes. Erythropoiesis is the most iron-consuming process to support hemoglobin production. Iron delivery is mediated via transferrin internalization by the endocytosis of transferrin receptor type 1 (TFR1), one of the most abundant membrane proteins of erythroblasts. A second transferrin receptor—TFR2—associates with the erythropoietin receptor and has been implicated in the regulation of erythropoiesis. In erythroblasts, both transferrin receptors adopt peculiarities such as an erythroid-specific regulation of TFR1 and a trafficking pathway reliant on TFR2 for iron. This review reports both trafficking and signaling functions of these receptors and reassesses the debated role of TFR2 in erythropoiesis in the light of recent findings. Potential therapeutic uses targeting the transferrin-TFR1 axis or TFR2 in hematological disorders are also discussed.
Highlights
Erythropoiesis is a highly dynamic process wherein hematopoietic stem cells (HSCs) present in the bone marrow give rise to 2 × 1011 red blood cells (RBCs) per day [1]
HSCs go through several differentiation steps to give rise to Burst Forming Unit–Erythroid cells (BFU-Es) which are entirely committed to the erythroid lineage
A higher affinity of TFR2 for N-loaded transferrin (N-Tf) compared to C-loaded transferrin (C-Tf) could lead to a higher recycling of TFR2 [31], which could lead to an increased expression of EPOR at cell surface and a higher responsiveness [10,55]
Summary
Erythropoiesis is a highly dynamic process wherein hematopoietic stem cells (HSCs) present in the bone marrow give rise to 2 × 1011 red blood cells (RBCs) per day [1]. This process involves several steps of differentiation, and is regulated by the niche and several cytokines and growth factors [2]. BFU-Es generate morphologically indistinguishable Colony Forming Unit–Erythroid cells (CFU-Es), whose proliferation capability is decreased At this stage of differentiation, cell survival and proliferation become reliant on the main erythroid regulator erythropoietin (EPO) and on its receptor (EPOR) [2]. An overview of these receptors as iron transporter and as mediator of cellular signaling pathway will be given, and their potential value as therapeutic targets in diseases affecting erythropoiesis and the iron metabolism will be highlighted
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