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

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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article numbere104270
JournalEMBO Journal
Volume39
Issue number8
DOIs
StatePublished - 15 Apr 2020

Funding

FundersFunder number
Generalitat de Catalunya, Agència de Gestió d'Ajuds Universitaris i de Recerca
Minhong Yan (Genentech), Georges Lacaud
Cancer Research UK
European Research Council341096, FJCI2014‐19870, BP 00021, SLT002/16/00070
Agència de Gestió d'Ajuts Universitaris i de RecercaPERIS‐SLT002/16/00299, 2017 SGR 135
Ministerio de Economía y CompetitividadSAF2016 ‐75613‐R
Institut Nacional d'Educacio Fisica de Catalunya, Generalitat de Catalunya

    Keywords

    • AGM
    • Dll4
    • HSC
    • Notch
    • hemogenic endothelium

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