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dc.contributor.authorPearson, Stella
dc.contributor.authorSroczynska, Patrycja
dc.contributor.authorLacaud, Georges
dc.contributor.authorKouskoff, Valerie
dc.date.accessioned2009-05-22T13:15:21Z
dc.date.available2009-05-22T13:15:21Z
dc.date.issued2008-04
dc.identifier.citationThe stepwise specification of embryonic stem cells to hematopoietic fate is driven by sequential exposure to Bmp4, activin A, bFGF and VEGF. 2008, 135 (8):1525-35 Developmenten
dc.identifier.issn0950-1991
dc.identifier.pmid18339678
dc.identifier.doi10.1242/dev.011767
dc.identifier.urihttp://hdl.handle.net/10541/68797
dc.description.abstractThe differentiation of embryonic stem (ES) cells offers a powerful approach to study mechanisms implicated in cell fate decision. A major hurdle, however, is to promote the directed and efficient differentiation of ES cells toward a specific lineage. Here, we define in serum-free media the minimal factor requirement controlling each step of the differentiation process, resulting in the production of highly enriched hematopoietic progenitors. Four factors - Bmp4, activin A, bFGF (Fgf2) and VEGF (VegfA) - are sufficient to drive the selective and efficient differentiation of mouse ES cells to hematopoiesis. Each of these factors appears to regulate a step of the process: Bmp4 promotes the very efficient formation of mesoderm; bFGF and activin A induce the differentiation of these mesodermal precursors to the hemangioblast fate; and VEGF is required for the production of fully committed hematopoietic progenitors. The stimulation of mesodermal precursors by bFGF and activin A switches on very rapidly the hematopoietic program, allowing us to dissect the molecular events leading to the formation of the hemangioblast. Runx1, Scl (Tal1) and Hhex expression is upregulated within 3 hours of stimulation, whereas upregulation of Lmo2 and Fli1 is observed later. Interestingly, increased expression levels of genes such as cMyb, Pu.1 (Sfpi1), Gata1 and Gata2 are not observed at the onset of hemangioblast commitment. This stepwise control of differentiation is extremely efficient, giving rise to a very high frequency of hematopoietic precursors, and provides an optimal system for understanding the molecular machineries involved in blood progenitor commitment.
dc.language.isoenen
dc.subject.meshActivins
dc.subject.meshAnimals
dc.subject.meshBasic Helix-Loop-Helix Transcription Factors
dc.subject.meshBone Morphogenetic Protein 4
dc.subject.meshBone Morphogenetic Proteins
dc.subject.meshCell Differentiation
dc.subject.meshCells, Cultured
dc.subject.meshCore Binding Factor Alpha 2 Subunit
dc.subject.meshCulture Media, Serum-Free
dc.subject.meshDNA-Binding Proteins
dc.subject.meshEmbryonic Stem Cells
dc.subject.meshFibroblast Growth Factor 2
dc.subject.meshGene Expression Regulation, Developmental
dc.subject.meshHematopoiesis
dc.subject.meshHematopoietic Stem Cells
dc.subject.meshHomeodomain Proteins
dc.subject.meshMetalloproteins
dc.subject.meshMice
dc.subject.meshProto-Oncogene Protein c-fli-1
dc.subject.meshProto-Oncogene Proteins
dc.subject.meshRecombinant Proteins
dc.subject.meshTranscription Factors
dc.subject.meshVascular Endothelial Growth Factor A
dc.titleThe stepwise specification of embryonic stem cells to hematopoietic fate is driven by sequential exposure to Bmp4, activin A, bFGF and VEGF.en
dc.typeArticleen
dc.contributor.departmentCancer Research UK, Paterson Institute for Cancer Research, Manchester University, Wilmslow Road, M20 4BX, Manchester, UK.en
dc.identifier.journalDevelopmenten
html.description.abstractThe differentiation of embryonic stem (ES) cells offers a powerful approach to study mechanisms implicated in cell fate decision. A major hurdle, however, is to promote the directed and efficient differentiation of ES cells toward a specific lineage. Here, we define in serum-free media the minimal factor requirement controlling each step of the differentiation process, resulting in the production of highly enriched hematopoietic progenitors. Four factors - Bmp4, activin A, bFGF (Fgf2) and VEGF (VegfA) - are sufficient to drive the selective and efficient differentiation of mouse ES cells to hematopoiesis. Each of these factors appears to regulate a step of the process: Bmp4 promotes the very efficient formation of mesoderm; bFGF and activin A induce the differentiation of these mesodermal precursors to the hemangioblast fate; and VEGF is required for the production of fully committed hematopoietic progenitors. The stimulation of mesodermal precursors by bFGF and activin A switches on very rapidly the hematopoietic program, allowing us to dissect the molecular events leading to the formation of the hemangioblast. Runx1, Scl (Tal1) and Hhex expression is upregulated within 3 hours of stimulation, whereas upregulation of Lmo2 and Fli1 is observed later. Interestingly, increased expression levels of genes such as cMyb, Pu.1 (Sfpi1), Gata1 and Gata2 are not observed at the onset of hemangioblast commitment. This stepwise control of differentiation is extremely efficient, giving rise to a very high frequency of hematopoietic precursors, and provides an optimal system for understanding the molecular machineries involved in blood progenitor commitment.


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