Notch ligand Dll4 impairs cell recruitment to aortic clusters and limits blood stem cell generation

Porcheri, Cristina; Golan, Ohad; Calero-Nieto, Fernando J.; Thambyrajah, Roshana; Ruiz-Herguido, Cristina; Wang, Xiaonan; Catto, Francesca; Guillén, Yolanda; Sinha, Roshani, 1989-; González, Jessica; Kinston, Sarah J.; Mariani, Samanta A.; Maglitto, Antonio; Vink, Chris S.; Dzierzak, Elaine; Charbord, Pierre; Göttgens, Bertie; Espinosa Blay, Lluís; Sprinzak, David; Bigas Salvans, Anna

Notch ligand Dll4 impairs cell recruitment to aortic clusters and limits blood stem cell generation

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dc.contributor.author Porcheri, Cristina
dc.contributor.author Golan, Ohad
dc.contributor.author Calero-Nieto, Fernando J.
dc.contributor.author Thambyrajah, Roshana
dc.contributor.author Ruiz-Herguido, Cristina
dc.contributor.author Wang, Xiaonan
dc.contributor.author Catto, Francesca
dc.contributor.author Guillén, Yolanda
dc.contributor.author Sinha, Roshani, 1989-
dc.contributor.author González, Jessica
dc.contributor.author Kinston, Sarah J.
dc.contributor.author Mariani, Samanta A.
dc.contributor.author Maglitto, Antonio
dc.contributor.author Vink, Chris S.
dc.contributor.author Dzierzak, Elaine
dc.contributor.author Charbord, Pierre
dc.contributor.author Göttgens, Bertie
dc.contributor.author Espinosa Blay, Lluís
dc.contributor.author Sprinzak, David
dc.contributor.author Bigas Salvans, Anna
dc.date.accessioned 2021-05-04T06:52:40Z
dc.date.available 2021-05-04T06:52:40Z
dc.date.issued 2020
dc.description.abstract Hematopoietic stem cells (HSCs) develop from the hemogenic endothelium in cluster structures that protrude into the embryonic aortic lumen. Although much is known about the molecular characteristics of the developing hematopoietic cells, we lack a complete understanding of their origin and the three-dimensional organization of the niche. Here, we use advanced live imaging techniques of organotypic slice cultures, clonal analysis, and mathematical modeling to show the two-step process of intra-aortic hematopoietic cluster (IACH) formation. First, a hemogenic progenitor buds up from the endothelium and undergoes division forming the monoclonal core of the IAHC. Next, surrounding hemogenic cells are recruited into the IAHC, increasing their size and heterogeneity. We identified the Notch ligand Dll4 as a negative regulator of the recruitment phase of IAHC. Blocking of Dll4 promotes the entrance of new hemogenic Gfi1+ cells into the IAHC and increases the number of cells that acquire HSC activity. Mathematical modeling based on our data provides estimation of the cluster lifetime and the average recruitment time of hemogenic cells to the cluster under physiologic and Dll4-inhibited conditions.
dc.description.sponsorship We thank Thomas Graf (CRG), Minhong Yan (Genentech), Georges Lacaud (CRUK Manchester Institut) and Ralf Adams (Max Planck Institute for Molecular Medicine, Münster) for important mice models and reagents. Thanks to Catherine Robin, Timo Zimmermann and, Raul Gómez-Riera for imaging advice. Thanks to the PRBB facilities: animal facility, flow cytometry, CNAGCRG genomics, confocal microscopy for critical technical assistance. Thanks to Marta Garrido and Luis Galán for experimental support and all the members of the lab for helpful critical discussions. This research was funded by the Ministerio de Economía y Competitividad (SAF2016 -75613-R) and Generalitat de Catalunya, Agència de Gestió d’Ajuds Universitaris i de Recerca (AGAUR) (2017 SGR 135) and PERIS-SLT002/16/00299 to AB and ERC AdG 341096 to ED. CP was a recipient of Juan de la Cierva fellowship (FJCI2014-19870), RT is a recipient of Beatriu de Pinos (2016 BP 00021), JG is a recipient of PERIS (SLT002/16/00070).
dc.format.mimetype application/pdf
dc.identifier.citation Porcheri C, Golan O, Calero-Nieto FJ, Thambyrajah R, Ruiz-Herguido C, Wang X, et al. Notch ligand Dll4 impairs cell recruitment to aortic clusters and limits blood stem cell generation. EMBO J. 2020 Apr 15; 39(8):e104270. DOI: 10.15252/embj.2019104270
dc.identifier.doi http://dx.doi.org/10.15252/embj.2019104270
dc.identifier.issn 0261-4189
dc.identifier.uri http://hdl.handle.net/10230/47298
dc.language.iso eng
dc.publisher Wiley-Blackwell
dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/SAF2016-75613-R
dc.rights This is the pre-peer reviewed version of the following article: Porcheri C, Golan O, Calero-Nieto FJ, Thambyrajah R, Ruiz-Herguido C, Wang X, et al. Notch ligand Dll4 impairs cell recruitment to aortic clusters and limits blood stem cell generation. EMBO J. 2020 Apr 15; 39(8):e104270, which has been published in final form at http://dx.doi.org/10.15252/embj.2019104270. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.subject.keyword AGM
dc.subject.keyword HSC
dc.subject.keyword Dll4
dc.subject.keyword Notch
dc.subject.keyword Hemogenic endothelium
dc.title Notch ligand Dll4 impairs cell recruitment to aortic clusters and limits blood stem cell generation
dc.type info:eu-repo/semantics/article
dc.type.version info:eu-repo/semantics/acceptedVersion

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