title: Skeletogenic phenotype of human Marfan embryonic stem cells faithfully phenocopied by patient-specific induced-pluripotent stem cells.
abstract: Marfan syndrome (MFS) is a heritable connective tissue disorder caused by mutations in the gene coding for FIBRILLIN-1 (FBN1), an extracellular matrix protein. MFS is inherited as an autosomal dominant trait and displays major manifestations in the ocular, skeletal, and cardiovascular systems. Here we report molecular and phenotypic profiles of skeletogenesis in tissues differentiated from human embryonic stem cells and induced pluripotent stem cells that carry a heritable mutation in FBN1. We demonstrate that, as a biological consequence of the activation of TGF-β signaling, osteogenic differentiation of embryonic stem cells with a FBN1 mutation is inhibited; osteogenesis is rescued by inhibition of TGF-β signaling. In contrast, chondrogenesis is not perturbated and occurs in a TGF-β cell-autonomous fashion. Importantly, skeletal phenotypes observed in human embryonic stem cells carrying the monogenic FBN1 mutation (MFS cells) are faithfully phenocopied by cells differentiated from induced pluripotent-stem cells derived independently from MFS patient fibroblasts. Results indicate a unique phenotype uncovered by examination of mutant pluripotent stem cells and further demonstrate the faithful alignment of phenotypes in differentiated cells obtained from both human embryonic stem cells and induced pluripotent-stem cells, providing complementary and powerful tools to gain further insights into human molecular pathogenesis, especially of MFS.
authors.affiliation: Department of Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA. quarto@unina.it
authors.forename: Natalina
authors.initials: N
authors.lastname: Quarto
authors.forename: Brian
authors.initials: B
authors.lastname: Leonard
authors.forename: Shuli
authors.initials: S
authors.lastname: Li
authors.forename: Melanie
authors.initials: M
authors.lastname: Marchand
authors.forename: Erica
authors.initials: E
authors.lastname: Anderson
authors.forename: Barry
authors.initials: B
authors.lastname: Behr
authors.forename: Uta
authors.initials: U
authors.lastname: Francke
authors.forename: Renee
authors.initials: R
authors.lastname: Reijo-Pera
authors.forename: Eric
authors.initials: E
authors.lastname: Chiao
authors.forename: Michael T
authors.initials: MT
authors.lastname: Longaker
mesh_terms: D001483:Base Sequence; D001842:Bone and Bones / Q000378:metabolism / Q000473:pathology*; D002454:Cell Differentiation; D020219:Chondrogenesis; D053595:Embryonic Stem Cells / Q000378:metabolism / Q000473:pathology*; D000071838:Fibrillin-1; D000071837:Fibrillins; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000473:pathology*; D008382:Marfan Syndrome / Q000378:metabolism / Q000473:pathology*; D008840:Microfilament Proteins / Q000235:genetics; D008969:Molecular Sequence Data; D010012:Osteogenesis; D010641:Phenotype; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism; D054392:Adipokines
chemical_list: D000071838:Fibrillin-1; D000071837:Fibrillins; D008840:Microfilament Proteins; D016212:Transforming Growth Factor beta; C000605722:FBN1 protein, human; D054392:Adipokines