Inhibition of endothelial ERK signalling by Smad1/5 is essential for haematopoietic stem cell emergence

The earliest HSCs are derived from haemogenic endothelium via endothelial-to-haematopoietic transition during vertebrate embryogenesis; however, the underlying mechanism is largely unclear. Here we show that interplay of Smad1/5 and ERK signalling is essential for haemogenic endothelium-based HSC emergence. Smad1/5 directly inhibits erk expression through recruiting HDAC1 to and inducing de-acetylation of the erk promoter in endothelial cells. Over-activated ERK signalling conferred by inhibition of Smad1/5 promotes the arterial endothelial cell fate and constitutively strengthens the tight junction between endothelial cells, thereby repressing the specification of haemogenic endothelium and the following endothelial-to-haematopoietic transition process. These findings provide new insights into the in vitro generation of transplantable HSCs for potential clinical applications. Vertebrate haematopoietic stem cells are produced from the haemogenic endothelium by an endothelial-to-haematopoietic transition. Here, the authors show that, in zebrafish and mice, this transition depends on interplay of Smad transcription factors and the ERK signalling pathway.