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