Inducible overexpression of RUNX1b/c in human embryonic stem cells blocks early hematopoiesis from mesoderm
- J Mol Cell Biol. 2017 Aug 1;9(4):262-273. doi: 10.1093/jmcb/mjx032.
- 1. Institute of Blood Transfusion, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Chengdu 610052, China.
- 2. State Key Laboratory of Biotherapy, Sichuan University, Chengdu 610065, China.
- 3. Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan.
- 4. State Key Laboratory of Experimental Hematology, CAMS & PUMC, Tianjin 300020, China.
RUNX1 is absolutely required for definitive hematopoiesis, but the function of RUNX1b/c, two isoforms of human RUNX1, is unclear. We established inducible RUNX1b/c-overexpressing human embryonic stem cell (hESC) lines, in which RUNX1b/c overexpression prevented the emergence of CD34+ cells from early stage, thereby drastically reducing the production of hematopoietic stem/progenitor cells. Simultaneously, the expression of hematopoiesis-related factors was downregulated. However, such blockage effect disappeared from day 6 in hESC/AGM-S3 cell 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.