The story of the E-cad, the β-cat, the FOX(O3) and the rat And their role in stress erythropoiesis

Erythropoiesis, or the generation of red blood cells (RBCs), is essential for oxygen transport throughout the body. During anemia, RBC production increases, in a process termed stress erythropoiesis. Although essential for recovery, the underlying molecular mechanisms are not fully understood. Therefore, we aimed to gain more insight into the regulation of stress erythropoiesis, and to identify pathways that may ultimately aid the development of novel therapeutic options for anemia. 
We identified E-cadherin as an important regulator of stress erythropoiesis. We showed that E-cadherin stabilizes β-catenin in human and rat erythroblasts. β-catenin, in turn, was shown to stimulate terminal erythroid maturation. Furthermore, E-cadherin and β-catenin were upregulated during hemolytic anemia in rats, suggesting a role in stress erythropoiesis. Moreover, we showed that the transcription factor FOXO3 contributes to terminal erythroid maturation, enucleation and hemoglobinization in primary human erythroblasts. Nevertheless, FOXO3 KO did not affect erythroid commitment or expansion, and despite the delay in differentiation, reticulocytes were formed, indicating that FOXO3 is important, but not essential for erythropoiesis.
To study E-cadherin in vivo, we developed a rat transplantation model using genetically modified hematopoietic stem and progenitor cells. This model demonstrated that loss of E-cadherin delays recovery of irradiation-induced anemia, and indicated that stress erythropoiesis in rats consists of two phases: expansion in bone marrow and spleen followed by accelerated terminal differentiation in bone marrow.
Together these findings provide insight into the molecular regulation of stress erythropoiesis and establish novel tools to study this process, eventually supporting the development of novel anemia therapies.