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From mesoderm to blood: the role of vasculature

English title From mesoderm to blood: the role of vasculature
Applicant Bertrand Julien
Number 166515
Funding scheme Project funding
Research institution Département de Pathologie et Immunologie Faculté de Médecine / CMU Université de Genève
Institution of higher education University of Geneva - GE
Main discipline Embryology, Developmental Biology
Start/End 01.04.2016 - 31.07.2019
Approved amount 388'680.00
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All Disciplines (2)

Discipline
Embryology, Developmental Biology
Cardiovascular Research

Keywords (6)

mesoderm patterning; hemangioblast; zebrafish; hematopoietic stem cells; hematopoiesis; hematopoietic niche

Lay Summary (French)

Lead
Notre tissu sanguin est constamment régénéré par une population rare de cellules souches hématopoïétiques (CSHs). Ces dernières sont produites uniquement au cours de la vie embryonnaire. Lorsque le tissu sanguin est malade (leucémie, anémie), on recourt à la transplantation de moelle osseuse, ou à la réparation par thérapie génique des CSHs. Dans un cas comme dans l’autre, il faut avoir recours à l’amplification ex vivo des CSHs. Notre laboratoire étudie les mécanismes qui participent à la production des CSHs ainsi qu’à leur amplification.
Lay summary

Contenu et objectifs du travail de recherche

Nos objectifs sont de caractériser les différentes étapes conduisant les premières cellules totipotentes de l’embryon à se différencier en cellules sanguines. Au cours du developpement embryonnaire, la formation des cellules sanguines est intimement liée au developpement du système vasculaire. Au cours des trois prochaines années, nous étudierons (1) comment les précurseurs du mésoderme se différencient en cellules vasculaires ou sanguines, (2) quels sont les mécanismes moléculaires impliques dans la spécification des cellules endothéliales hématogènes en CSHs, et (3) comment les cellules vasculaires servent de niche aux CSHs afin de les faire proliférer. Nous étudierons tous ces aspects dans l’embryon de zebrafish. En effet, ce vertébré aquatique est un excellent model pour la biologie de développement et son système sanguin est très similaire au système sanguin de la souris ou de l’Homme. De plus, cet embryon est transparent, ce qui permet une observation directe du développement hémato-vasculaire.

 

Contexte scientifique et social du projet de recherche

Avec la réalisation de ce projet, nous allons mieux comprendre la formation des cellules souches sanguines et du système sanguin, tant au niveau cellulaire que moléculaire. Grace au degré de conservation entre le zébrafish et les mammifères, ces nouvelles données pourront être utilisées dans un contexte clinique, et permettront la régénération du tissu sanguin de patients atteints de graves déficits immunitaires ou leucémies.

Direct link to Lay Summary Last update: 29.03.2016

Responsible applicant and co-applicants

Employees

Publications

Publication
bif1 , a new BMP signaling inhibitor, regulates embryonic hematopoiesis in the zebrafish
Ghersi Joey J., Mahony Christopher B., Bertrand Julien Y. (2019), bif1 , a new BMP signaling inhibitor, regulates embryonic hematopoiesis in the zebrafish, in Development, 146(6), dev164103-dev164103.
How HSCs Colonize and Expand in the Fetal Niche of the Vertebrate Embryo: An Evolutionary Perspective
Mahony Christopher B., Bertrand Julien Y. (2019), How HSCs Colonize and Expand in the Fetal Niche of the Vertebrate Embryo: An Evolutionary Perspective, in Frontiers in Cell and Developmental Biology, 7, NA-NA.
KLF4-Induced Connexin40 Expression Contributes to Arterial Endothelial Quiescence
Denis Jean-François, Diagbouga Mannekomba R., Molica Filippo, Hautefort Aurélie, Linnerz Tanja, Watanabe Masakatsu, Lemeille Sylvain, Bertrand Julien Y., Kwak Brenda R. (2019), KLF4-Induced Connexin40 Expression Contributes to Arterial Endothelial Quiescence, in Frontiers in Physiology, 10, NA-NA.
Embryonic Microglia Derive from Primitive Macrophages and Are Replaced by cmyb-Dependent Definitive Microglia in Zebrafish
Ferrero Giuliano, Mahony Christopher B., Dupuis Eléonore, Yvernogeau Laurent, Di Ruggiero Elodie, Miserocchi Magali, Caron Marianne, Robin Catherine, Traver David, Bertrand Julien Y., Wittamer Valérie (2018), Embryonic Microglia Derive from Primitive Macrophages and Are Replaced by cmyb-Dependent Definitive Microglia in Zebrafish, in Cell Reports, 24(1), 130-141.
Oncostatin M and Kit-Ligand Control Hematopoietic Stem Cell Fate during Zebrafish Embryogenesis
Mahony Christopher B., Pasche Corentin, Bertrand Julien Y. (2018), Oncostatin M and Kit-Ligand Control Hematopoietic Stem Cell Fate during Zebrafish Embryogenesis, in Stem Cell Reports, 10(6), 1920-1934.
Ndrg1b and fam49ab modulate the PTEN pathway to control T-cell lymphopoiesis in the zebrafish.
LiRoman, TraverDavid, MatthesThomas, BertrandJulien Y (2016), Ndrg1b and fam49ab modulate the PTEN pathway to control T-cell lymphopoiesis in the zebrafish., in BLOOD, 128(26), 3052-3060.
tfec controls the hematopoietic stem cell vascular niche during zebrafish embryogenesis
Mahony C. B., Fish R. J., Pasche C., Bertrand J. Y. (2016), tfec controls the hematopoietic stem cell vascular niche during zebrafish embryogenesis, in Blood, 128(10), 1336-1345.

Collaboration

Group / person Country
Types of collaboration
Wittamer group / Université Libre de Bruxelles Belgium (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Swiss Zebrafish meeting 10 Talk given at a conference DLC1 is a negative regulator of directed endothelial cell migration during embryonic vascular development 18.05.2018 Berne, Switzerland Linnerz Tanja;
Cardiovascular research meeting 2018 Talk given at a conference Elucidating the role of dlc1 and dlc3 during cardiovascular development 15.03.2018 Fribourg, Switzerland Bertrand Julien;
Zebrafish Disease Modeling 10 (ZDM10) Talk given at a conference TFEC, a master regulator of the HSC niche during embryogenesis 05.08.2017 San Diego, CA, United States of America Bertrand Julien;
EMBL conference: Hematopoietic Stem Cells, from the Embryo to the Aging Organism Talk given at a conference TFEC controls the HSC niche during zebrafish embryogenesis 03.06.2016 Heidelberg, Germany Bertrand Julien;


Associated projects

Number Title Start Funding scheme
146527 From mesoderm to blood: decoding the cellular and molecular pathways 01.04.2013 Project funding
184814 Hematopoietic Stem Cells and their niche: origin and maturation during embryonic development 01.08.2019 Project funding
184814 Hematopoietic Stem Cells and their niche: origin and maturation during embryonic development 01.08.2019 Project funding

Abstract

BackgroundHematopoietic Stem Cells (HSCs), or blood stem cells, are the lineal founder of all our circulating blood cells, involved in tissue oxygenation as well as immunity. HSCs represent a rare population of progenitors, and are very tightly regulated at several levels. Hence, any dysregulation at the cell or non-cell autonomous level can lead to fatal outcomes, e.g. leukemias or severe immunodeficiencies. Most of these diseases now rely on regenerative therapy for treatment: when the system is malfunctioning, either the HSC pool can be replaced (bone marrow transplantation) or HSCs themselves can be corrected (gene therapy). In either situation, protocols rely on the capability to make new HSCs (from induced pluripotent stem cells) or to amplify ex vivo a pool of existing HSCs. We use the zebrafish model to study these two aspects of HSC biology. The zebrafish model offers many advantages over the mouse model as fertilization occurs externally, thus allowing to manipulating embryos, which are optically transparent. Moreover, a high degree of conservation exists between zebrafish and mammals, allowing the translation of new findings in the zebrafish model towards mammalian system, and even into clinical trials.In this proposal, we will use the zebrafish model to understand several aspects of HSC biology. We will first try to understand the molecular mechanisms involved in the initial expansion of the HSC pool specified during embryogenesis. In parallel, we will study HSC specification itself, first by investigating new pathways involved in HSC emergence from the hemogenic endothelium, then by trying to understand how this hemogenic endothelium is differentiating from the initial pool of progenitors located in the lateral plate mesoderm. This new approach should allow us to find new molecular and cellular pathways involved in HSC biology, thus offering new perspectives in our effort to develop regenerative medicine against several blood disorders.Specific AimsThis project has three specific aims:1-To understand the molecular mechanisms controlling the identity of the HSC niche in the caudal hematopoietic tissue.2-To characterize the cellular and molecular aspects of the endothelial-to-hematopoiesis transition, in the context of definitive hematopoiesis.3-To decipher the function of new genes of interest in the specification of lateral plate mesoderm towards vascular and blood lineages.Expected value of the proposed projectThe discovery of new molecular pathways is important to our understanding of HSC biology. Our approach using zebrafish allows us to investigate HSC biology at stages that are hardly manageable when using mouse models. Our strategy has proven efficient as we already discovered new genes with novel functions. We will continue our effort to gain to characterize more genes of unknown functions involved in HSC biology.
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