title: Sphingosine 1-phosphate induces differentiation of mesoangioblasts towards smooth muscle. A role for GATA6.
abstract: Different cells can contribute to repair following vascular injury by differentiating into smooth muscle (SM) cells; however the extracellular signals involved are presently poorly characterized. Mesoangioblasts are progenitor cells capable of differentiating into various mesoderm cell types including SM cells. In this study the biological action exerted by the pleiotropic sphingolipid sphingosine 1-phosphate (S1P) in human mesoangioblasts has been initially investigated by cDNA microarray analysis. Obtained data confirmed the anti-apoptotic action of this sphingolipid and identified for the first time a strong differentiating action toward SM cells. Quantitative mRNA and protein analysis corroborated the microarray results demonstrating enhanced expression of myogenic marker proteins and regulation of the expression of transcription factor GATA6 and its co-regulator, LMCD1. Importantly, GATA6 up-regulation induced by S1P was responsible for the enhanced expression of SM-specific contractile proteins. Moreover, by specific gene silencing experiments GATA6 was critical in the pro-differentiating activity of the cytokine TGFβ. Finally, the pharmacological inhibition of endogenous S1P formation in response to TGFβ abrogated GATA6 up-regulation, supporting the view that the S1P pathway plays a physiological role in mediating the pro-myogenic effect of TGFβ. This study individuates GATA6 as novel player in the complex transcriptional regulation of mesoangioblast differentiation into SM cells and highlights a role for S1P to favour vascular regeneration.
authors.affiliation: Dipartimento di Scienze Biochimiche, Università di Firenze, Firenze, Italia.
authors.forename: Chiara
authors.initials: C
authors.lastname: Donati
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Marseglia
authors.forename: Alberto
authors.initials: A
authors.lastname: Magi
authors.forename: Simona
authors.initials: S
authors.lastname: Serratì
authors.forename: Francesca
authors.initials: F
authors.lastname: Cencetti
authors.forename: Caterina
authors.initials: C
authors.lastname: Bernacchioni
authors.forename: Genni
authors.initials: G
authors.lastname: Nannetti
authors.forename: Matteo
authors.initials: M
authors.lastname: Benelli
authors.forename: Silvia
authors.initials: S
authors.lastname: Brunelli
authors.forename: Francesca
authors.initials: F
authors.lastname: Torricelli
authors.forename: Giulio
authors.initials: G
authors.lastname: Cossu
authors.forename: Paola
authors.initials: P
authors.lastname: Bruni
mesh_terms: D015153:Blotting, Western; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D002478:Cells, Cultured; D056970:Co-Repressor Proteins; D050993:GATA6 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D060588:LIM Domain Proteins; D008246:Lysophospholipids / Q000494:pharmacology*; D008856:Microscopy, Fluorescence; D032389:Myocytes, Smooth Muscle / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D034741:RNA, Small Interfering; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D013234:Stem Cells / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D056970:Co-Repressor Proteins; D050993:GATA6 Transcription Factor; C494759:GATA6 protein, human; D060588:LIM Domain Proteins; C406239:LMCD1 protein, human; D008246:Lysophospholipids; D034741:RNA, Small Interfering; C060506:sphingosine 1-phosphate; D013110:Sphingosine