| Autor: |
Porcheri, Cristina, Golan, Ohad, Calero‐Nieto, Fernando J, Thambyrajah, Roshana, Ruiz‐Herguido, Cristina, Wang, Xiaonan, Catto, Francesca, Guillén, Yolanda, Sinha, Roshani, González, Jessica, Kinston, Sarah J, Mariani, Samanta A, Maglitto, Antonio, Vink, Chris S, Dzierzak, Elaine, Charbord, Pierre, Göttgens, Bertie, Espinosa, Lluis, Sprinzak, David, Bigas, Anna |
| Předmět: |
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| Zdroj: |
EMBO Journal; Apr2020, Vol. 39 Issue 8, p1-19, 19p, 8 Graphs |
| Abstrakt: |
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. Synopsis: In this study, combined in vivo imaging, clonal analyses and modeling reveal that formation of embryonic hematopoietic cell clusters from the mouse aortic endothelium is a sequential process, which involves Notch signaling‐dependent integration of hemogenic cells. Nascent E10.5 aortic cell clusters are proliferative and monoclonal.Advanced hematopoietic cell clusters become polyclonal via recruitment of neighboring endothelial cells.Expression of Notch ligand Dll4 is increased in nascent hematopoietic cell clusters.Blockage of Dll4 in vivo results in perturbed Notch signaling, precocious cluster increase and compromised progression to blood stem cells. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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