Cis inhibition of NOTCH1 through JAGGED1 sustains embryonic hematopoietic stem cell fate
Thambyrajah, Roshana (Institut Hospital del Mar d'Investigacions Mèdiques)
Maqueda, Maria (Institut Germans Trias i Pujol)
Neo, Wen Hao (The University of Manchester)
Imbach, Kathleen (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Guillén, Yolanda (Institut Hospital del Mar d'Investigacions Mèdiques)
Grases Mendoza, Daniela (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Fadlullah, Zaki (The University of Manchester)
Gambera, Stefano (Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares)
Matteini, Fernando (Program for advancing the Clinical Translation of Regenerative Medicine of Catalonia)
Wang, Xiaonan (Shanghai Jiao Tong University)
Calero-Nieto, Fernando (Cambridge Biomedical Campus)
Esteller, M (Universitat de Barcelona. Departament de Ciències Fisiològiques)
Florian, María Carolina (Centro de Investigacion Biomedica en Red (Madrid))
Porta-Pardo, Eduard (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Benedito, Rui (Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares)
Göttgens, Berthold (Cambridge Biomedical Campus (Regne Unit))
Lacaud, Georges (Cancer Research UK The University of Manchester)
Espinosa, Lluis (Centro de Investigacion Biomedica en Red (Madrid))
Bigas Salvans, Anna (Centro de Investigacion Biomedica en Red (Madrid))

Date:	2024
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.
Grants:	Agencia Estatal de Investigación SAF2016-75613-R Agencia Estatal de Investigación PID2019-104695RB-I00 Generalitat de Catalunya SLT002/16/00299 Agencia Estatal de Investigación PID2020-120252RB-I00 Agència de Gestió d'Ajuts Universitaris i de Recerca 2021/SGR-00039 Generalitat de Catalunya BP2016 (00021) Generalitat de Catalunya BP/MSCA 2018 (00034)
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Aorta ; Arteries ; Cell Differentiation ; Gonads ; Hematopoietic Stem Cells ; Mesonephros ; Receptor, Notch1
Published in:	Nature communications, Vol. 15 Núm. 1 (december 2024) , p. 1604, ISSN 2041-1723

DOI: 10.1038/s41467-024-45716-y
PMID: 38383534

18 p, 6.7 MB

The record appears in these collections:
Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut d'Investigació en Ciencies de la Salut Germans Trias i Pujol (IGTP) > Josep Carreras Leukaemia Research Institute
Articles > Research articles
Articles > Published articles