title: Activation of the TGFβ pathway impairs endothelial to haematopoietic transition.
abstract: The endothelial to haematopoietic transition (EHT) is a key developmental process where a drastic change of endothelial cell morphology leads to the formation of blood stem and progenitor cells during embryogenesis. As TGFβ signalling triggers a similar event during embryonic development called epithelial to mesenchymal transition (EMT), we hypothesised that TGFβ activity could play a similar role in EHT as well. We used the mouse embryonic stem cell differentiation system for in vitro recapitulation of EHT and performed gain and loss of function analyses of the TGFβ pathway. Quantitative proteomics analysis showed that TGFβ treatment during EHT increased the secretion of several proteins linked to the vascular lineage. Live cell imaging showed that TGFβ blocked the formation of round blood cells. Using gene expression profiling we demonstrated that the TGFβ signalling activation decreased haematopoietic genes expression and increased the transcription of endothelial and extracellular matrix genes as well as EMT markers. Finally we found that the expression of the transcription factor Sox17 was up-regulated upon TGFβ signalling activation and showed that its overexpression was enough to block blood cell formation. In conclusion we showed that triggering the TGFβ pathway does not enhance EHT as we hypothesised but instead impairs it.
authors.affiliation: European Molecular Biology Laboratory, Mouse Biology Unit, Via Ercole Ramarini 32, 00015 Monterotondo, Italy.
authors.forename: Özge
authors.initials: Ö
authors.lastname: Vargel
authors.affiliation: European Molecular Biology Laboratory, Mouse Biology Unit, Via Ercole Ramarini 32, 00015 Monterotondo, Italy.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: European Molecular Biology Laboratory, Mouse Biology Unit, Via Ercole Ramarini 32, 00015 Monterotondo, Italy.
authors.forename: Kinga
authors.initials: K
authors.lastname: Kosim
authors.affiliation: European Molecular Biology Laboratory, Mouse Biology Unit, Via Ercole Ramarini 32, 00015 Monterotondo, Italy.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Ganter
authors.affiliation: European Molecular Biology Laboratory, Genome Biology Unit, Meyerhofstraße 1, 69117 Heidelberg, Germany.
authors.forename: Sophia
authors.initials: S
authors.lastname: Foehr
authors.affiliation: European Molecular Biology Laboratory, Mouse Biology Unit, Via Ercole Ramarini 32, 00015 Monterotondo, Italy.
authors.forename: Yannicka
authors.initials: Y
authors.lastname: Mardenborough
authors.affiliation: European Molecular Biology Laboratory, Mouse Biology Unit, Via Ercole Ramarini 32, 00015 Monterotondo, Italy.
authors.forename: Maya
authors.initials: M
authors.lastname: Shvartsman
authors.affiliation: European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SD, United Kingdom.
authors.forename: Anton J
authors.initials: AJ
authors.lastname: Enright
authors.affiliation: European Molecular Biology Laboratory, Genome Biology Unit, Meyerhofstraße 1, 69117 Heidelberg, Germany.
authors.forename: Jeroen
authors.initials: J
authors.lastname: Krijgsveld
authors.affiliation: European Molecular Biology Laboratory, Mouse Biology Unit, Via Ercole Ramarini 32, 00015 Monterotondo, Italy.
authors.forename: Christophe
authors.initials: C
authors.lastname: Lancrin
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D054338:Cell Transdifferentiation / Q000187:drug effects; D003114:Colony-Forming Units Assay; D042783:Endothelial Cells / Q000166:cytology* / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D024002:HMGB Proteins / Q000235:genetics / Q000378:metabolism; D006410:Hematopoiesis / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D018919:Neovascularization, Physiologic / Q000187:drug effects; D055760:SOXF Transcription Factors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D059467:Transcriptome; D016212:Transforming Growth Factor beta / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D024002:HMGB Proteins; D055760:SOXF Transcription Factors; C511606:Sox17 protein, mouse; D016212:Transforming Growth Factor beta