title: TGFβ1 inhibits lymphatic endothelial cell differentiation from mouse embryonic stem cells.
abstract: The lymphatic vasculature is essential for the maintenance of tissue fluid, immune surveillance, and dissemination of metastasis. Recently, several models for lymphatic vascular research and markers specific for lymphatic endothelium have been characterized. Despite these significant achievements, our understanding of the early lymphatic development is still rather limited. The purpose of the study was to further define early lymphatic differentiation regulatory pathways. In the present study, we have developed conditions leading to lymphatic endothelial cell differentiation under both serum-rich and serum-free conditions, using the coculture system of Flk-1-positive vascular precursors derived from murine embryonic stem (ES) cells grown on an OP9 stromal cell layer. In this work, we also identified Transforming Growth Factor-β1 (TGFβ1) as a negative regulator of lymphvasculogenesis from ES-derived vascular progenitors. Finally, we could show that TGFβ1 addition decreases COUP-TFII and Sox18 mRNA levels, which are two transcription factors known to be involved in early lymphatic endothelial differentiation. Taken together these findings support the concept that manipulating the TGFβ signaling pathway may represent an interesting target to favor lymphatic endothelial cell expansion for cell replacement strategies.
authors.affiliation: Inserm, U1036, Grenoble, France. daniel.vittet@cea.fr
authors.forename: Daniel
authors.initials: D
authors.lastname: Vittet
authors.forename: Galina
authors.initials: G
authors.lastname: Merdzhanova
authors.forename: Marie-Hélène
authors.initials: MH
authors.lastname: Prandini
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Feige
authors.forename: Sabine
authors.initials: S
authors.lastname: Bailly
mesh_terms: D000818:Animals; D051837:COUP Transcription Factor II / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D019070:Cell Lineage / Q000235:genetics; D018920:Coculture Techniques; D016895:Culture Media, Serum-Free; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000502:physiology; D042783:Endothelial Cells / Q000166:cytology / Q000502:physiology; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D006023:Glycoproteins / Q000378:metabolism; D026901:Membrane Transport Proteins; D051379:Mice; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D055760:SOXF Transcription Factors / Q000378:metabolism; D015398:Signal Transduction; D017154:Stromal Cells / Q000166:cytology; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D051837:COUP Transcription Factor II; D016895:Culture Media, Serum-Free; D006023:Glycoproteins; D026901:Membrane Transport Proteins; D011994:Recombinant Proteins; D055760:SOXF Transcription Factors; D053773:Transforming Growth Factor beta1; D040301:Vascular Endothelial Growth Factor Receptor-2; C497587:Nr2f2 protein, mouse; C490653:Sox18 protein, mouse; C492273:LYVE1 protein, mouse