Cis inhibition of NOTCH1 through JAGGED1 sustains embryonic hematopoietic stem cell fate
Roshana Thambyrajah, María Maqueda, Wen Hao Neo, Kathleen J. Imbach, Yolanda Guillén, Daniela Grases, Zaki Fadlullah, Stefano Gambera, Francesca Matteini, Xiaonan Wang, Fernando J. Calero‐Nieto, Manel Esteller, Maria Carolina Florian, Eduard Porta‐Pardo, Rui Benedito, Berthold Göttgens, Georges Lacaud, Lluı́s Espinosa, Anna Bigas
Abstract
Hematopoietic stem cells (HSCs) develop from the hemogenic endothelium (HE) in the aorta- gonads-and mesonephros (AGM) region and reside within Intra-aortic hematopoietic clusters (IAHC) along with hematopoietic progenitors (HPC). The signalling mechanisms that distinguish HSCs from HPCs are unknown. Notch signaling is essential for arterial specification, IAHC formation and HSC activity, but current studies on how Notch segregates these different fates are inconsistent. We now demonstrate that Notch activity is highest in a subset of, GFI1 + , HSC-primed HE cells, and is gradually lost with HSC maturation. We uncover that the HSC phenotype is maintained due to increasing levels of NOTCH1 and JAG1 interactions on the surface of the same cell (cis) that renders the NOTCH1 receptor from being activated. Forced activation of the NOTCH1 receptor in IAHC activates a hematopoietic differentiation program. Our results indicate that NOTCH1-JAG1 cis-inhibition preserves the HSC phenotype in the hematopoietic clusters of the embryonic aorta.