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

Research output: Contribution to journalArticle

  • 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

Related Edinburgh Organisations

Original languageEnglish
Pages (from-to)e104270
JournalEMBO Journal
Early online date9 Mar 2020
DOIs
Publication statusE-pub ahead of print - 9 Mar 2020

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.

ID: 141253642