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Embryonic Stem Cells/Induced Pluripotent Stem Cells
Version of Record online: 27 NOV 2012
Copyright © 2012 AlphaMed Press
Volume 30, Issue 12, pages 2709–2719, December 2012
How to Cite
Quarto, N., Li, S., Renda, A. and Longaker, M. T. (2012), Exogenous Activation of BMP-2 Signaling Overcomes TGFβ-Mediated Inhibition of Osteogenesis in Marfan Embryonic Stem Cells and Marfan Patient-Specific Induced Pluripotent Stem Cells. STEM CELLS, 30: 2709–2719. doi: 10.1002/stem.1250
Author contributions: Quarto N, conception and design, collection and/or assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript, Li S.: collection of data, renda A.: final approval of manuscript, administrative support, longaker M.: Financial support, Final approval of manuscript.
Disclosure of potential conflicts of interest is found at the end of this article.
First published online in STEM CELLSEXPRESS October 4, 2012.
- Issue online: 27 NOV 2012
- Version of Record online: 27 NOV 2012
- Accepted manuscript online: 4 OCT 2012 08:42AM EST
- Manuscript Accepted: 23 AUG 2012
- Manuscript Received: 12 JUN 2012
- National Institutes of Health. Grant Numbers: NIH-U01 HL099776, RC1 HL100490, RC2 DE020771
- California Institute Regenerative Medicine. Grant Number: #RL1-00662-1
- Embryonic stem cells;
- Induced pluripotent Stem cells;
- Signal transduction;
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 TGFβ signaling. Mutations in FBN1 are therefore associated with increased activity and bioavailability of TGF-β1, which is suspected to be the basis for phenotypical similarities of FBN1 mutations in MFS and mutations in the receptors for TGFβ 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 TGFβ and BMP signaling. Our results revealed that enhanced activation of TGFβ signaling observed in MFS cells decreased their endogenous BMP signaling. Moreover, exogenous BMP antagonized the enhanced TGFβ 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. STEM CELLS 2012;30:2709–2719