Cis inhibition of NOTCH1 through JAGGED1 sustains embryonic hematopoietic stem cell fate

• Published in: Nature communications Vol. 15; no. 1; p. 1604
• Main Authors: Thambyrajah, Roshana, Maqueda, Maria, Neo, Wen Hao, Imbach, Kathleen, Guillén, Yolanda, Grases, Daniela, Fadlullah, Zaki, Gambera, Stefano, Matteini, Francesca, Wang, Xiaonan, Calero-Nieto, Fernando J., Esteller, Manel, Florian, Maria Carolina, Porta, Eduard, Benedito, Rui, Göttgens, Berthold, Lacaud, Georges, Espinosa, Lluis, Bigas, Anna
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 21-02-2024; Nature Publishing Group; Nature Portfolio
• Subjects: 13/21; 13/31; 13/51; 13/89; 38/91; 631/136/232; 631/136/532/1542; 631/80/86; 64; 64/60; Aorta; Cell fate; Clusters; Coronary vessels; Embryo cells; Endothelial cells; Endothelium; Gonads; Hematopoietic stem cells; Hemopoiesis; Humanities and Social Sciences; Jagged1 protein; multidisciplinary; Notch1 protein; Phenotypes; Receptors; Science; Science (multidisciplinary); Stem cells
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-45716-y

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.
Notch signaling is critical for HSC emergence. Here, the authors identify a sub-set of hemogenic endothelial cells with high Notch activity that it is gradually shut down through cis inhibition of NOTCH1 by JAG1, and report that this process sustains HSC.