Skeletogenic phenotype of human Marfan embryonic stem cells faithfully phenocopied by patient-specific induced-pluripotent stem cells

Proc Natl Acad Sci U S A. 2012 Jan 3;109(1):215-20. doi: 10.1073/pnas.1113442109. Epub 2011 Dec 16.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Bone and Bones / metabolism
  • Bone and Bones / pathology*
  • Cell Differentiation
  • Chondrogenesis
  • Embryonic Stem Cells / metabolism
  • Embryonic Stem Cells / pathology*
  • Fibrillin-1
  • Fibrillins
  • Humans
  • Induced Pluripotent Stem Cells / pathology*
  • Marfan Syndrome / metabolism
  • Marfan Syndrome / pathology*
  • Microfilament Proteins / genetics
  • Molecular Sequence Data
  • Osteogenesis
  • Phenotype
  • Signal Transduction
  • Transforming Growth Factor beta / metabolism


  • FBN1 protein, human
  • Fibrillin-1
  • Fibrillins
  • Microfilament Proteins
  • Transforming Growth Factor beta