An iPSC-derived vascular model of Marfan syndrome identifies key mediators of smooth muscle cell death.
Alessandra GranataFelipe SerranoWilliam George BernardMadeline McNamaraLucinda LowPriya SastrySanjay SinhaPublished in: Nature genetics (2016)
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.
Keyphrases
- extracellular matrix
- induced pluripotent stem cells
- transforming growth factor
- cell death
- smooth muscle
- epithelial mesenchymal transition
- cell cycle arrest
- endothelial cells
- crispr cas
- oxidative stress
- genome wide
- endoplasmic reticulum stress
- transcription factor
- aortic dissection
- aortic aneurysm
- aortic valve
- heart failure
- coronary artery
- dna methylation
- signaling pathway
- pluripotent stem cells
- single cell
- small molecule
- pulmonary hypertension
- cell proliferation
- pi k akt
- drug induced