Abstract The aryl hydrocarbon receptor (AHR) plays an important role during mammalian embryo development. Inhibition of AHR signaling promotes the development of hematopoietic stem/progenitor cells. AHR also regulates the functional maturation of blood cells, such as T cells and megakaryocytes. However, little is known about the role of AHR modulation during the development of erythroid cells. In this study, we used the AHR antagonist StemRegenin 1 (SR1) and the AHR agonist 2, 3, 7, 8-tetrachlorodibenzo- p- dioxin (TCDD) during different stages of human erythropoiesis to elucidate the function of AHR. We found that antagonizing AHR signaling improved the production of human embryonic stem cell (hESC)-derived erythrocytes and enhanced erythroid terminal differentiation. RNA-sequencing showed that SR1 treatment of proerythroblasts upregulated the expression of erythrocyte differentiation-related genes and downregulated actin organization-associated genes. We found that SR1 promoted F-actin remodeling in terminally differentiated erythrocytes, favoring the maturation of the cytoskeleton and enucleation. We demonstrated that the effects of AHR inhibition on erythroid maturation resulted from an increase in F-actin remodeling. Our findings help uncover the mechanism for AHR-mediated human erythroid cell differentiation. We also provide a new approach toward the large-scale production of functionally mature hPSC-derived erythrocytes for use in translational applications.

Inhibition of aryl hydrocarbon receptor signaling promotes the terminal differentiation of human erythrocytes