Hematopoietic stem cells (HSCs) are a group of hematopoietic progenitor cells that can differentiate into all kinds of mature blood cells (including erythroid, myeloid and lymphoid cells) that circulate through the body to maintain normal physiology functions. Hematopoiesis in vertebrates comprises two waves (the primitive wave and the definitive wave) and HSCs are only specified from the the definitive one. Ncor2 has been reported to be necessary for primitive hematopoiesis but its role in definitive hematopoiesis especially in HSC emergence remains elusive. 

The Hematopoiesis and Cardiovascular Development Group led by Prof. Feng Liu found that ncor2 is expressed in the aorta-gonad-mesonephros (AGM) and the HSCs of zebrafish. ncor2 deficiency led to the severe decrease of HSCs and T cells. Further experiments revealed that Ncor2 cooperates with Hdac3 to repress the transcription of fos. ncor2 knockdown upregulated fos transcription by modulating the acetylation level in the fos promoter region, which then enhanced Vegfd signaling. Consequently, the augmented Vegfd signaling induced Notch signaling to promote the arterial endothelial fate, therefore possibly repressing the hemogenic endothelial specification which is a prerequisite for HSC emergence. Thus, our findings identify a novel regulatory mechanism for Ncor2 through Fos-Vegfd-Notch signaling cascade during HSC development in zebrafish embryos. This work broadens our vision on the mechanism of HSC emergence and may provide new clues for the in vitro expansion of therapeutic HSCs.

This research was supported by grants from the National Basic Research Program of China, the National Natural Science Foundation of China, and the Strategic Priority Research Program of the Chinese Academy of Sciences.

Website: http://bloodjournal.hematologylibrary.org/content/early/2014/07/08/blood-2013-11-541391