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

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-Pardo, Eduard; Benedito, Rui; Göttgens, Berthold; Lacaud, Georges; Espinosa Blay, Lluís; Bigas Salvans, Anna

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

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dc.contributor.author Thambyrajah, Roshana
dc.contributor.author Maqueda, Maria
dc.contributor.author Neo, Wen Hao
dc.contributor.author Imbach, Kathleen
dc.contributor.author Guillén, Yolanda
dc.contributor.author Grases, Daniela
dc.contributor.author Fadlullah, Zaki
dc.contributor.author Gambera, Stefano
dc.contributor.author Matteini, Francesca
dc.contributor.author Wang, Xiaonan
dc.contributor.author Calero-Nieto, Fernando J.
dc.contributor.author Esteller, Manel
dc.contributor.author Florian, Maria Carolina
dc.contributor.author Porta-Pardo, Eduard
dc.contributor.author Benedito, Rui
dc.contributor.author Göttgens, Berthold
dc.contributor.author Lacaud, Georges
dc.contributor.author Espinosa Blay, Lluís
dc.contributor.author Bigas Salvans, Anna
dc.date.accessioned 2024-10-30T07:16:55Z
dc.date.available 2024-10-30T07:16:55Z
dc.date.issued 2024
dc.description.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.
dc.description.sponsorship We thank Sarah Bray and David Sprinzak for critical discussions about cis interactions. We thank Genentech for kindly gifting the anti-JAG1 and anti-NOTCH1 antibodies. We thank all members of Espinosa and Bigas laboratories for helpful discussions and technical support. All illustrations in the manuscript were created with BioRender.com. We also thank the animal facility, FACS facility, and genomic facility of the PRBB and CRUK Manchester Institute for their technical support. This work was funded by grants from SAF2016-75613-R and PID2019-104695RB-I00 from Agencia Estatal de Investigación (AEI) and SLT002/16/00299 from Department of Health, Generalitat de Cataluña and 2021 SGR 00039 from AGAUR, Generalitat de Catalunya. The work in the G.L. laboratory is supported by Blood Cancer UK (19014) and Cancer Research UK Manchester Institute Core Grant (C5759/A27412). The work in R.B. laboratory was supported by a grant from the Ministerio de Ciencia e Innovación (MCIN - PID2020-120252RB-I00). RT is a recipient of BP2016 (00021) and BP/MSCA 2018 (00034) fellowship programs from Generalitat de Catalunya/MSCA. E.P. is a recipient of RYC2019-026415-I. M.M. is a recipient of a grant from the Instituto Carlos III, grant number CA22/00011 (cofunded by the European Social Fund Plus, ESF+, and by the European Union).
dc.format.mimetype application/pdf
dc.identifier.citation Thambyrajah 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-y
dc.identifier.doi http://dx.doi.org/10.1038/s41467-024-45716-y
dc.identifier.issn 2041-1723
dc.identifier.uri http://hdl.handle.net/10230/68393
dc.language.iso eng
dc.publisher Nature Research
dc.relation.ispartof Nat Commun. 2024 Feb 21;15(1):1604
dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/SAF2016-75613-R
dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2019-104695RB-I00
dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2020-120252RB-I00
dc.rights © 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/.
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.rights.uri http://creativecommons.org/licenses/by/4.0/
dc.subject.keyword Cell signalling
dc.subject.keyword Haematopoietic stem cells
dc.subject.keyword Haematopoiesis
dc.title Cis inhibition of NOTCH1 through JAGGED1 sustains embryonic hematopoietic stem cell fate
dc.type info:eu-repo/semantics/article
dc.type.version info:eu-repo/semantics/publishedVersion

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