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


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Authors
Golan, Ohad 
Calero-Nieto, Fernando J 
Thambyrajah, Roshana 
Ruiz-Herguido, Cristina 
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.

Description
Keywords
AGM, HSC, Dll4, Notch, hemogenic endothelium, Adaptor Proteins, Signal Transducing, Animals, Aorta, Calcium-Binding Proteins, Cell Division, Endothelial Progenitor Cells, Female, Hemangioblasts, Hematopoietic Stem Cells, Mice, Mice, Inbred C57BL, Models, Theoretical
Journal Title
EMBO J
Conference Name
Journal ISSN
0261-4189
1460-2075
Volume Title
39
Publisher
Springer Science and Business Media LLC
Rights
All rights reserved
Sponsorship
Medical Research Council (MC_PC_12009)
Medical Research Council (MR/M008975/1)
Medical Research Council (MC_PC_17230)
Wellcome Trust, MRC