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

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...

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Detalles Bibliográficos
Autores: 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
Tipo de recurso: artículo
Estado:Versión aceptada para publicación
Fecha de publicación:2020
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:10230/47298
Acceso en línea:http://hdl.handle.net/10230/47298
http://dx.doi.org/10.15252/embj.2019104270
Access Level:acceso abierto
Palabra clave:AGM
HSC
Dll4
Notch
Hemogenic endothelium
Descripción
Sumario: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.

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