Michael Longaker

Publication Details

  • Exogenous Activation of BMP-2 Signaling Overcomes TGF beta-Mediated Inhibition of Osteogenesis in Marfan Embryonic Stem Cells and Marfan Patient-Specific Induced Pluripotent Stem Cells STEM CELLS Quarto, N., Li, S., Renda, A., Longaker, M. T. 2012; 30 (12): 2709-2719


    Marfan syndrome (MFS) is a hereditary disease caused by mutations in the gene encoding Fibrillin-1 (FBN1) and characterized by a number of skeletal abnormalities, aortic root dilatation, and sometimes ectopia lentis. Although the molecular pathogenesis of MFS was attributed initially to a structural weakness of the fibrillin-rich microfibrils within the extracellular matrix, more recent results have documented that many of the pathogenic abnormalities in MFS are the result of alterations in TGF? signaling. Mutations in FBN1 are therefore associated with increased activity and bioavailability of TGF-?1, which is suspected to be the basis for phenotypical similarities of FBN1 mutations in MFS and mutations in the receptors for TGF? in Marfan syndrome-related diseases. We have previously demonstrated that unique 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 (MFSiPS) derived independently from MFS patient fibroblasts. In this study, we aimed to determine further the biochemical features of transducing signaling(s) in MFS stem cells and MFSiPS cells highlighting a crosstalk between TGF? and BMP signaling. Our results revealed that enhanced activation of TGF? signaling observed in MFS cells decreased their endogenous BMP signaling. Moreover, exogenous BMP antagonized the enhanced TGF? signaling in both MFS stem cells and MFSiPS cells therefore, rescuing their ability to undergo osteogenic differentiation. This study advances our understanding of molecular mechanisms underlying the pathogenesis of bone loss/abnormal skeletogenesis in human diseases caused by mutations in FBN1.

    View details for DOI 10.1002/stem.1250

    View details for Web of Science ID 000311493600011

    View details for PubMedID 23037987

Stanford Medicine Resources:

Footer Links: