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

作　　者：Yijin Chen Yong Dong Xulin Lu Wanjing Li Yimeng Zhang Bin Mao Xu Pan Xiaohong Li Ya Zhou Quanming An Fangxin Xie Shihui Wang Yuan Xue Xinping Cai Mowen Lai Qiongxiu Zhou Yan Yan Ruohan Fu Hong Wang Tatsutoshi Nakahata Xiuli An Lihong Shi Yonggang Zhang Feng Ma 

机构地区：[1]Institute of Blood Transfusion,Chinese Academy of Medical Sciences&Peking Union Medical College(CAMS&PUMC),Chengdu 610052,China [2]State Key Laboratory of Experimental Hematology,Institute of Hematology and Blood Diseases Hospital,CAMS&PUMC,Tianjin 300020,China [3]School of Life Sciences,Zhengzhou University,Zhengzhou 450001,China [4]Department of Obstetrics and Gynecology,Jinjiang Maternity and Child Health Hospital,Chengdu 610065,China [5]Center for iPS Cell Research and Application(CiRA),Kyoto University,Kyoto 606-8507,Japan [6]Laboratory of Membrane Biology,New York Blood Center,New York,NY 10065,USA

出　　处：《Journal of Molecular Cell Biology》2022年第2期18-31,共14页分子细胞生物学报（英文版）

基　　金：supported by the National Basic Research Program(973 Program,2015CB964902);the National Natural Science Foundation of China(H81170466 and H81370597);the CAMS Initiatives for Innovative Medicine(2016-I2M-1-018,2019-I2M-1-006,and 2017-I2M-2005)to F.M.,the National Natural Science Foundation of China Youth Fund(82000119)to Yonggang Zhang.

摘　　要：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 AHRmediated 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.

关 键 词：ERYTHROBLAST AHR SR-1 human pluripotent stem cells DIFFERENTIATION 

分 类 号：Q813[生物学—生物工程]