Résumé :
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During embryonic development and embryonic stem cell (ESC) differentiation, the different cells forming the mature heart arise from the differentiation of two types of multipotent cardiovascular progenitors (MCPs). Using mouse embryonic stem cells in which Mesp1 expression can be temporally regulated, we found that transient expression of Mesp1 dramatically accelerates and enhances MCP specification and cardiovascular differentiation through an intrinsic and cellular autonomous mechanism. Mesp1 acts as a key regulator of MCP specification by rapidly and directly activates the expression of a discrete set of genes belonging to the core cardiac transcriptional machinery. Mesp1 also directly represses the expression of key genes regulating other cell fates. These results demonstrate that Mesp1 acts as a key regulatory switch during cardiovascular specification, residing at the top of the transcriptional hierarchy responsible for cardiovascular cell fate specification1. A key question is whether these two sources of MCPs arise from the differentiation of a common progenitor. To address this question, we engineered a Mesp1-GFP reporter ESCs to isolate the earliest MCPs during ESC differentiation. Mesp1-GFP cells are strongly enriched for MCPs, presenting the ability to differentiate into multiple cardiovascular cells of both heart field lineages in vitro and in vivo. Transcriptional profiling of Mesp1-GFP cells uncovers cell surface markers expressed by MCPs allowing their prospective isolation. Mesp1 is required for MCPs specification and the expression of key cardiovascular transcription factors. Isl1, a marker of second heart field progenitors, is expressed in a subset of early Mesp1 expressing cells and acts together with Mesp1 to promote cardiovascular differentiation. Our study identifies the early MCPs residing at the top of the cellular hierarchy of the different cardiovascular lineages during ESC differentiation2. Altogether our studies demonstrate a key role of Mesp1 during the early step of MCP specification and early cardiovascular lineage commitment and provide novel methods for generating cardiovascular cells during ESC differentiation, which open new avenues for cardiac cellular therapy in humans3.This work was supported by the Belgian FNRS, the European Research Council (ERC) and the EMBO Young Investigator Program.References1. Bondue, A. et al. Mesp1 acts as a master regulator of multipotent cardiovascular progenitor specification. Cell Stem Cell 3, 69-84 (2008).2. Bondue, A. et al. Defining the earliest step of cardiovascular progenitor specification during embryonic stem cell differentiation. J Cell Biol 192, 751-65 (2011).3. Bondue, A. & Blanpain, C. Mesp1: a key regulator of cardiovascular lineage commitment. Circ Res 107, 1414-27 (2010).
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