Alpha lipoic acid promotes development of hematopoietic progenitors derived from human embryonic stem cells by antagonizing ROS signals

Journal of Leukocyte Biology: An Official Publication of the Reticuloendothelial Society

article

Yong Dong¹  Ju Bai¹  Yimeng Zhang¹  Ya Zhou¹  Xu Pan¹  Xiaohong Li¹  Qiongxiu Zhou¹  Yijin Chen¹  Mowen Lai¹  Bin Mao¹  Guohui Bian¹  Jia Feng¹  Fangxin Xie¹  Bo Chen¹  Tatsutoshi Nakahata²  Yonggang Zhang¹  Feng Ma¹ 

[1] Center for Stem Cell Research and Application, Institute of Blood Transfusion, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC);Center for iPS Cell Research and Application (CiRA), Kyoto University;State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, CAMS & PUMC

关键词: alpha lipoic acid;    endothelial-to-hematopoietic transition (EHT);    hematopoiesis;    hematopoietic stem/progenitor cells;    human pluripotent stem cells (hPSCs);    ROS;   

DOI  :  10.1002/JLB.1A0520-179R

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

Antagonism of ROS signaling can inhibit cell apoptosis and autophagy, thus favoring the maintenance and expansion of hematopoietic stem cells. Alpha lipoic acid (ALA), a small antioxidant molecule, affects cell apoptosis by lowering the ROS level. In this study, we show that ALA promoted production of human pluripotent stem cells (hPSCs) derived hemogenic endothelial cells and hematopoietic stem/progenitor cells in vitro. Transcriptome analysis of hPSCs derived hemogenic endothelial cells showed that ALA promoted endothelial-to-hematopoietic transition by up-regulating RUNX1, GFI1, GFI1B, MEIS2, and HIF1A and down-regulating SOX17, TGFB1, TGFB2, TGFB3, TGFBR1, and TGFBR2. ALA also up-regulated sensor genes of ROS signals, including HIF1A, FOXO1, FOXO3, ATM, PETEN, SIRT1, and SIRT3, during the process of hPSCs derived hemogenic endothelial cells generation. However, in more mature hPSC-derived hematopoietic stem/progenitor cells, ALA reduced ROS levels and inhibited apoptosis. In particular, ALA enhanced development of hPSCs derived hematopoietic stem/progenitor cells by up-regulating HIF1A in response to a hypoxic environment. Furthermore, addition of ALA in ex vivo culture greatly improved the maintenance of functional cord blood HSCs by in vivo transplantation assay. Our findings support the conjecture that ALA plays an important role in efficient regeneration of hematopoietic stem/progenitor cells from hPSCs and maintenance of functional HSCs, providing insight into understanding of regeneration of early hematopoiesis for engineering clinically useful hPSCs derived hematopoietic stem/progenitor cells transplantation. Thus, ALA can be used in the study of hPSCs derived HSCs.

【 授权许可】

CC BY