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

[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.

[学科分类] 生理学

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