Recapitulating and Correcting Marfan Syndrome in a Cellular Model

文献类型： 外文期刊

第一作者： Park, Jung Woo

作者： Park, Jung Woo;Yan, Li;Li, Enqin;Jiang, Bin;Zhang, Zhenwu;Xu, Ren-He;Stoddard, Chris;Wang, Xiaofang;Crandall, Leann;Robinson, Tiwanna;Denton, Kyle;Martins-Taylor, Kristen;Yee, Siu-Pok;Xu, Ren-He;Yue, Zhichao;Chang, Yuxiao;Nie, Hong;Gu, Feng;Gu, Feng;Gu, Feng;Si, Wei;Xie, Ting;Yue, Lixia

作者机构：

关键词： Marfan syndrome;human pluripotent stem cells;disease modeling;genome editing;osteogenesis;smooth muscle

期刊名称：INTERNATIONAL JOURNAL OF BIOLOGICAL SCIENCES （ 影响因子：6.58； 五年影响因子：6.478 ）

ISSN： 1449-2288

年卷期： 2017 年 13 卷 5 期

页码：

收录情况： SCI

摘要： 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.

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