Int J Biol Sci 2017; 13(5):588-603. doi:10.7150/ijbs.19517
Recapitulating and Correcting Marfan Syndrome in a Cellular Model
1. Faculty of Health Sciences, University of Macau, Taipa, Macau, China;
Marfan syndrome (MFS) is a connective tissue disorder caused by mutations in FBN1 gene, which encodes a key extracellular matrix protein FIBRILLIN-1. The haplosufficiency of FBN1 has been implicated in pathogenesis of MFS with manifestations primarily in cardiovascular, muscular, and ocular tissues. Due to limitations in animal models to study the late-onset diseases, human pluripotent stem cells (PSCs) offer a homogeneic tool for dissection of cellular and molecular pathogenic mechanism for MFS in vitro. Here, we first derived induced PSCs (iPSCs) from a MFS patient with a FBN1 mutation and corrected the mutation, thereby generating an isogenic “gain-of-function” control cells for the parental MFS iPSCs. Reversely, we knocked out FBN1 in both alleles in a wild-type (WT) human embryonic stem cell (ESC) line, which served as a loss-of-function model for MFS with the WT cells as an isogenic control. Mesenchymal stem cells derived from both FBN1-mutant iPSCs and -ESCs demonstrated reduced osteogenic differentiation and microfibril formation. We further demonstrated that vascular smooth muscle cells derived from FBN1-mutant iPSCs showed less sensitivity to carbachol as demonstrated by contractility and Ca2+ influx assay, compared to the isogenic controls cells. These findings were further supported by transcriptomic anaylsis of the cells. Therefore, this study based on both gain- and loss-of-function approaches confirmed the pathogenetic role of FBN1 mutations in these MFS-related phenotypic changes.
Keywords: Marfan syndrome, human pluripotent stem cells, disease modeling, genome editing, osteogenesis, smooth muscle.
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How to cite this article:
Park JW, Yan L, Stoddard C, Wang X, Yue Z, Crandall L, Robinson T, Chang Y, Denton K, Li E, Jiang B, Zhang Z, Martins-Taylor K, Yee SP, Nie H, Gu F, Si W, Xie T, Yue L, Xu RH. Recapitulating and Correcting Marfan Syndrome in a Cellular Model. Int J Biol Sci 2017; 13(5):588-603. doi:10.7150/ijbs.19517. Available from http://www.ijbs.com/v13p0588.htm