title: Dickkopf Homolog 3 Induces Stem Cell Differentiation into Smooth Muscle Lineage via ATF6 Signalling.
abstract: Smooth muscle cells (SMCs) are a key component of healthy and tissue engineered vessels and play a crucial role in vascular development and the pathogenic events of vascular remodeling i.e. restenosis. However, the cell source from which they can be isolated is limited. Embryonic stem (ES) cells that have the remarkable capability to differentiate into vascular SMCs in response to specific stimuli provide a useful model for studying SMC differentiation. Previous studies suggested that dickkopf homolog 3 (DKK3) has a role in human partially induced pluripotent stem cell to SMC differentiation. Here, we demonstrate that the expression of DKK3 is essential for the expression of SMC markers and myocardin at both the mRNA and protein levels during mouse ES cell differentiation into SMCs (ESC-SMC differentiation). Overexpression of DKK3 leads to further up-regulation of the aforementioned markers. Further investigation indicates that DKK3 added as a cytokine activates activating transcription factor 6 (ATF6), leading to the increased binding of ATF6 on the myocardin promoter and increased its expression. In addition, inhibition of extracellular signal-regulated kinases 1/2 (ERK1/2) promotes the expression of ATF6 and leads to further increase of myocardin transcription. Our findings offer a novel mechanism by which DKK3 regulates ESC-SMC differentiation by activating ATF6 and promoting myocardin expression.
authors.affiliation: From the Cardiovascular Division, King's College London BHF Centre, London SE5 9NU, United Kingdom and the Institute of Bioengineering, Queen Mary University of London, London E1 4NS, United Kingdom.
authors.forename: Xiaocong
authors.initials: X
authors.lastname: Wang
authors.affiliation: From the Cardiovascular Division, King's College London BHF Centre, London SE5 9NU, United Kingdom and.
authors.forename: Eirini
authors.initials: E
authors.lastname: Karamariti
authors.affiliation: From the Cardiovascular Division, King's College London BHF Centre, London SE5 9NU, United Kingdom and.
authors.forename: Russell
authors.initials: R
authors.lastname: Simpson
authors.affiliation: the Institute of Bioengineering, Queen Mary University of London, London E1 4NS, United Kingdom wen.wang@qmul.ac.uk.
authors.forename: Wen
authors.initials: W
authors.lastname: Wang
authors.affiliation: From the Cardiovascular Division, King's College London BHF Centre, London SE5 9NU, United Kingdom and qingbo.xu@kcl.ac.uk.
authors.forename: Qingbo
authors.initials: Q
authors.lastname: Xu
mesh_terms: D051702:Activating Transcription Factor 6 / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001665:Binding Sites; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D019070:Cell Lineage / Q000187:drug effects / Q000235:genetics; D004622:Embryo, Mammalian; D053595:Embryonic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D005419:Flavonoids / Q000494:pharmacology; D018507:Gene Expression Regulation, Developmental; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009687:Nuclear Proteins / Q000819:agonists / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D015534:Trans-Activators / Q000819:agonists / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000099251:Myocardin
chemical_list: D051702:Activating Transcription Factor 6; D048868:Adaptor Proteins, Signal Transducing; D005419:Flavonoids; D036341:Intercellular Signaling Peptides and Proteins; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D009687:Nuclear Proteins; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D015534:Trans-Activators; D000099251:Myocardin; C497112:Atf6 protein, mouse; C405061:Dkk3 protein, mouse; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
keywords: cardiovascular disease; cytokine; differentiation; myocardin; smooth muscle; stem cells