title: An iPSC-derived vascular model of Marfan syndrome identifies key mediators of smooth muscle cell death.
abstract: Marfan syndrome (MFS) is a heritable connective tissue disorder caused by mutations in FBN1, which encodes the extracellular matrix protein fibrillin-1. To investigate the pathogenesis of aortic aneurysms in MFS, we generated a vascular model derived from human induced pluripotent stem cells (MFS-hiPSCs). Our MFS-hiPSC-derived smooth muscle cells (SMCs) recapitulated the pathology seen in Marfan aortas, including defects in fibrillin-1 accumulation, extracellular matrix degradation, transforming growth factor-β (TGF-β) signaling, contraction and apoptosis; abnormalities were corrected by CRISPR-based editing of the FBN1 mutation. TGF-β inhibition rescued abnormalities in fibrillin-1 accumulation and matrix metalloproteinase expression. However, only the noncanonical p38 pathway regulated SMC apoptosis, a pathological mechanism also governed by Krüppel-like factor 4 (KLF4). This model has enabled us to dissect the molecular mechanisms of MFS, identify novel targets for treatment (such as p38 and KLF4) and provided an innovative human platform for the testing of new drugs.
authors.affiliation: Stroke Research Group, Department of Clinical Neurosciences, Cambridge Biomedical Campus, University of Cambridge, Cambridge, UK.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Granata
authors.affiliation: Anne McLaren Laboratory, Wellcome Trust-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK.|Division of Cardiovascular Medicine, University of Cambridge, Cambridge, UK.
authors.forename: Felipe
authors.initials: F
authors.lastname: Serrano
authors.affiliation: Anne McLaren Laboratory, Wellcome Trust-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK.|Division of Cardiovascular Medicine, University of Cambridge, Cambridge, UK.
authors.forename: William George
authors.initials: WG
authors.lastname: Bernard
authors.affiliation: Anne McLaren Laboratory, Wellcome Trust-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK.|Division of Cardiovascular Medicine, University of Cambridge, Cambridge, UK.|British Heart Foundation Oxbridge Centre for Regenerative Medicine, University of Cambridge, Cambridge, UK.
authors.forename: Madeline
authors.initials: M
authors.lastname: McNamara
authors.affiliation: Division of Cardiovascular Medicine, University of Cambridge, Cambridge, UK.
authors.forename: Lucinda
authors.initials: L
authors.lastname: Low
authors.affiliation: Anne McLaren Laboratory, Wellcome Trust-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK.|Division of Cardiovascular Medicine, University of Cambridge, Cambridge, UK.|Papworth Hospitals NHS Foundation Trust, Cambridge, UK.
authors.forename: Priya
authors.initials: P
authors.lastname: Sastry
authors.affiliation: Anne McLaren Laboratory, Wellcome Trust-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK.|Division of Cardiovascular Medicine, University of Cambridge, Cambridge, UK.|British Heart Foundation Oxbridge Centre for Regenerative Medicine, University of Cambridge, Cambridge, UK.
authors.forename: Sanjay
authors.identifier: 0000-0001-5900-1209
authors.initials: S
authors.lastname: Sinha
mesh_terms: D001014:Aortic Aneurysm / Q000378:metabolism / Q000473:pathology*; D017209:Apoptosis; D000071838:Fibrillin-1 / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism / Q000473:pathology*; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D008382:Marfan Syndrome / Q000378:metabolism / Q000473:pathology*; D008954:Models, Biological; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000473:pathology*; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000071838:Fibrillin-1; C000715467:KLF4 protein, human; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D016212:Transforming Growth Factor beta; D048051:p38 Mitogen-Activated Protein Kinases