Advances in understanding the mechanisms of erythropoiesis in homeostasis and disease

Abstract

Summary Anaemia or decreased blood haemoglobin is the most common blood disorder often characterized by reduced red blood cell (RBC) numbers. RBCs are produced from differentiation and commitment of haematopoietic stem cells to the erythroid lineage by a process called erythropoiesis. Coordination of erythropoietin receptor signalling with several erythroid transcription factors including GATA1 is essential for this process. A number of additional players that are critical for RBC production have been identified in recent years. Major technological advances, such as the development of RNA interference, genetically modified animals, including zebrafish, and imaging flow cytometry have led to these discoveries; the emergence of -omics approaches in combination with the optimization of ex vivo erythroid cultures have also produced a more comprehensive understanding of erythropoiesis. Here we summarize studies describing novel regulators of erythropoiesis that modulate erythroid cell production in the context of human erythroid disorders involving hypoxia, iron regulation, immune-related molecules, and the transcription factor FOXO3.

Regulation of GATA1 levels in erythropoiesis

“…The diversity of mature blood cells derives from a common progenitor, the hematopoietic stem cell (HSC), which undergoes a series of commitment and differentiation steps in response to specific stimuli in specialized tissue microenvironments (e.g., bone marrow and thymus), to generate not only the circulating blood cells (white blood cells, red blood cells, and platelets), but also the immune and nonimmune organ resident immune cells . Among the circulating blood cells, the highly specialized, oxygen‐carrying, enucleated erythroid (red blood) cells must be produced daily at high rates, according to a very specialized and well‐characterized cell differentiation program, which includes progressive size reduction, cell cycle arrest, massive synthesis of globin chains, and enucleation . In this respect, GATA1 has been acknowledged as the master transcriptional regulator of erythropoiesis, controlling all aspects of differentiation, survival, and cell cycle arrest .…”

“…[2][3][4] Among the circulating blood cells, the highly specialized, oxygen-carrying, enucleated erythroid (red blood) cells must be produced daily at high rates, according to a very specialized and well-characterized cell differentiation program, which includes progressive size reduction, cell cycle arrest, massive synthesis of globin chains, and enucleation. [5][6][7] In this respect, GATA1 has been acknowledged as the master transcriptional regulator of erythropoiesis, controlling all aspects of differentiation, survival, and cell cycle arrest. 8,9 Maintaining GATA1 protein homeostasis has been shown to be a highly regulated process in erythropoiesis, with deregulation being a major factor in ineffective erythropoiesis or leukemic transformation in hematological disease.…”

Oxidative Stress and Iron Overload in β-Thalassemia: An Overview

“…A combination of drugs affecting both the oxidative stress and the iron overload can give an effective outcome. Forkhead-box-O3 (Foxo3) is a critical transcription factor that protects the cell from oxidative stress by upregulating antioxidant enzymes during early stages of erythropoiesis [50]. At early stages, Foxo3 is phosphorylated by proteins of the EPOR-P13K/AKT/mTOR signaling pathway and is translocated out of the nucleus, where it remains inactivated.…”

99mTc‐labeled rHuEpo for imaging of the erythropoietin receptor in tumors

“…[1][2][3] Thus, recombinant human erythropoietin (rHuEpo) is the most widely used cytokine for treating anemia, especially in chemotherapy-induced anemia. There is an intricate network of interactions between various humoral factors and cytokines regulating the production of RBCs.…”

“…In turn, this results in the proliferation and terminal differentiation of erythroid precursor cells and provides protection from RBC precursor apoptosis. [1][2][3] Thus, recombinant human erythropoietin (rHuEpo) is the most widely used cytokine for treating anemia, especially in chemotherapy-induced anemia. 4 However, a number of studies have demonstrated that Epo treatment compromises overall survival rate, and EpoR is expressed in various types of cancer cells 5 such as breast cancer, 6 gastric adenocarcinoma, 7 and melanoma.…”