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Inhibition of aryl hydrocarbon receptor signaling promotes the terminal differentiation of human erythroblasts
Yijin Chen1 , Yong Dong1 , Xulin Lu2 , Wanjing Li1 , Yimeng Zhang1 , Bin Mao1 , Xu Pan1 , Xiaohong Li1 , Ya Zhou1 , Quanming An1 , Fangxin Xie1 , Shihui Wang3 , Yuan Xue1 , Xinping Cai1 , Mowen Lai1 , Qiongxiu Zhou1 , Yan Yan4 , Ruohan Fu4 , Hong Wang1 , Tatsutoshi Nakahata5 , Xiuli An6 , Lihong Shi2 , Yonggang Zhang1,* , Feng Ma1,2,*
1Institute of Blood Transfusion, Chengdu 610052, China
2State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, CAMS & PUMC, Tianjin 300020, China
3School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China
4Department of Obstetrics and Gynecology, Jinjiang Maternity and Child Health Hospital, Chengdu 610065, China
5Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan
6Laboratory of Membrane Biology, New York Blood Center, New York, NY 10065, USA
*Correspondence to:Yonggang Zhang , Feng Ma ,
J Mol Cell Biol, Volume 14, Issue 2, February 2022, mjac001,
Keyword: erythroblast, AHR, SR-1, human pluripotent stem cells, differentiation

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 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 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 accelerated F-actin remodeling in terminally differentiated erythrocytes, favoring their maturation of the cytoskeleton and enucleation. We demonstrated that the effects of AHR inhibition on erythroid maturation were associated with 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 human pluripotent stem cell-derived erythrocytes for use in translational applications.