RUNXI is absolutely required for definitive hematopoiesis, but the function of RUNXlb/c, two isoforms of human RUNX1, is unclear. We established inducible RUNXlb/c-overexpressing human embryonic stem cell （hESC） lin...RUNXI is absolutely required for definitive hematopoiesis, but the function of RUNXlb/c, two isoforms of human RUNX1, is unclear. We established inducible RUNXlb/c-overexpressing human embryonic stem cell （hESC） lines, in which RUNXlb/c overexpression prevented the emergence of CD34＋ cells from early stage, thereby drastically reducing the production of hematopoi- etic stem/prognnitor cells. Simultaneously, the expression of hematopoiesis-related factors was downregulated. However, such blockage effect disappeared from day 6 in hESC/AGM-S3 ceU co-cultures, proving that the blockage occurred before the generation of hemogenic endothelial cells. This blockage was partially rescued by RepSox, an inhibitor of the transforming growth factor （TGF）-β signaling pathway, indicating a close relationship between RUNX1b/c and TGF-β pathway. Our results suggest a unique inhibitory function of RUNX1b/c in the development of early hematopoiesis and may aid further understanding of its biological function in normal and diseased models.展开更多
基金This work was supported by the National Program on Key Basic Research Project of China （973 Program 2015CB964902）, the National Natural Science Foundation of China （NSFC H81170466 and H81370597）, and the CAMS Initiatives for Innovative Medicine （2016-12M-1-018） awarded to F.M.
文摘RUNXI is absolutely required for definitive hematopoiesis, but the function of RUNXlb/c, two isoforms of human RUNX1, is unclear. We established inducible RUNXlb/c-overexpressing human embryonic stem cell （hESC） lines, in which RUNXlb/c overexpression prevented the emergence of CD34＋ cells from early stage, thereby drastically reducing the production of hematopoi- etic stem/prognnitor cells. Simultaneously, the expression of hematopoiesis-related factors was downregulated. However, such blockage effect disappeared from day 6 in hESC/AGM-S3 ceU co-cultures, proving that the blockage occurred before the generation of hemogenic endothelial cells. This blockage was partially rescued by RepSox, an inhibitor of the transforming growth factor （TGF）-β signaling pathway, indicating a close relationship between RUNX1b/c and TGF-β pathway. Our results suggest a unique inhibitory function of RUNX1b/c in the development of early hematopoiesis and may aid further understanding of its biological function in normal and diseased models.
