Thambyrajah, RoshanaMaqueda, MariaNeo, Wen HaoImbach, KathleenGuillén, YolandaGrases, DanielaFadlullah, ZakiGambera, StefanoMatteini, FrancescaWang, XiaonanCalero-Nieto, Fernando J.Esteller, ManelFlorian, Maria CarolinaPorta-Pardo, EduardBenedito, RuiGöttgens, BertholdLacaud, GeorgesEspinosa Blay, LluísBigas Salvans, Anna2024-10-302024-10-302024Thambyrajah R, Maqueda M, Neo WH, Imbach K, Guillén Y, Grases D, et al. Cis inhibition of NOTCH1 through JAGGED1 sustains embryonic hematopoietic stem cell fate. Nat Commun. 2024 Feb 21;15(1):1604. DOI: 10.1038/s41467-024-45716-y2041-1723http://hdl.handle.net/10230/68393Hematopoietic 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.application/pdfeng© The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.info:eu-repo/semantics/articlehttp://dx.doi.org/10.1038/s41467-024-45716-yCell signallingHaematopoietic stem cellsHaematopoiesisinfo:eu-repo/semantics/openAccess