Opening the window for endothelial-to-hematopoietic transition

Abstract

Definitive long-term hematopoietic stem cells (LT-HSCs) arise during embryogenesis in a process termed endothelial-to-hematopoietic transition (EHT), in which specialized hemogenic endothelial cells (HECs) transform into hematopoietic cells. The transcription factor RUNX1 marks HECs and is essential for EHT. Ectopic RUNX1 expression in non-HECs is sufficient to convert them into HECs. However, the conversion efficiency depends on the developmental timing of expression. In this issue of Genes & Development, Howell and colleagues (pp. 1475-1489) leverage this observation to further understand how RUNX1 mediates EHT. They engineered mice that ectopically express RUNX1 in endothelial cells at different developmental time points and doses. They then performed chromatin accessibility and other analyses and correlate this with hemogenic potential. They found that RUNX1 collaborates with TGFβ signaling transcription factors to drive chromatin accessibility changes that specify HECs. They also highlight interesting parallels between EHT and endothelial-to-mesenchymal transition (EndoMT), which occurs during cardiac development. The results of Howell and colleagues provide new mechanistic insights into EHT and take us one step closer to generating patient-specific LT-HSCs from induced pluripotent stem cells.

Keywords: RUNX1; TGFβ; endothelial-to-hematopoietic transition; endothelial-to-mesenchymal transition; hematopoiesis; hemogenic endothelium.

Figure 1.

Parallels between endothelial-to-hematopoietic transition (EHT) and endothelial-to-mesenchymal transition (EndoMT). EHT and EndoMT occur at similar times during embryonic development. Both are driven by RUNX family transcription factors and involve TGF-β and NOTCH signaling. Howell et al. (2021) now show that RUNX1 collaborates with TGFβ signaling transcription factors AP-1 and SMAD2/3 to open chromatin at sites involved in EHT. Genes selectively accessible during EHT include Twist, Snai1, and Hey1/2, which play functional roles in EndoMT. (Figure created in BioRender).