Induced pluripotent stem cells from patients with human fibrodysplasia ossificans progressiva show increased mineralization and cartilage formation.
Induced pluripotent stem cells from patients with human fibrodysplasia ossificans progressiva show increased mineralization and cartilage formation.
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DOI：
10.1186/1750-1172-8-190
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发表时间：
2013-12-09
影响因子：
3.7
通讯作者：
Hsiao EC
中科院分区：
文献类型：
--
作者：
Matsumoto Y;Hayashi Y;Schlieve CR;Ikeya M;Kim H;Nguyen TD;Sami S;Baba S;Barruet E;Nasu A;Asaka I;Otsuka T;Yamanaka S;Conklin BR;Toguchida J;Hsiao EC
软组织中软骨内骨形成的异常激活会导致与残疾和疼痛相关的重大医学疾病。骨形态发生蛋白 (BMP) 1 型受体 ACVR1 的过度活跃突变会导致进行性骨化性纤维发育不良 (FOP)，这是一种罕见的遗传性疾病，其特征是软组织进行性骨化。然而，具体的细胞机制尚不清楚。此外，从 FOP 患者身上获取组织样本的困难以及 FOP 小鼠模型的局限性阻碍了我们剖析 FOP 发病机制的能力。为了应对这些挑战并开发“培养皿中的疾病模型”，我们通过两种不同的方法（逆转录病毒整合或无整合附加型载体）从正常和 FOP 真皮成纤维细胞中创建了人类诱导多能干细胞（iPS 细胞）。我们测试了 FOP 与对照 iPS 细胞对软骨内骨形成不同步骤的贡献能力是否不同。值得注意的是，FOP iPS 细胞在体外表现出矿化增加和软骨形成增强。 BMP 信号传导小分子抑制剂 DMH1 可以抑制矿化表型。我们的结果表明，FOP ACVR1 R206H 突变有利于软骨形成并增加体外矿物质沉积。我们的研究结果建立了用于体外实验的 FOP 疾病细胞模型，并为使用人类 iPS 细胞模型了解人类骨骼疾病提供了概念验证。
Abnormal activation of endochondral bone formation in soft tissues causes significant medical diseases associated with disability and pain. Hyperactive mutations in the bone morphogenetic protein (BMP) type 1 receptor ACVR1 lead to fibrodysplasia ossificans progressiva (FOP), a rare genetic disorder characterized by progressive ossification in soft tissues. However, the specific cellular mechanisms are unclear. In addition, the difficulty obtaining tissue samples from FOP patients and the limitations in mouse models of FOP hamper our ability to dissect the pathogenesis of FOP. To address these challenges and develop a “disease model in a dish”, we created human induced pluripotent stem cells (iPS cells) derived from normal and FOP dermal fibroblasts by two separate methods, retroviral integration or integration-free episomal vectors. We tested if the ability to contribute to different steps of endochondral bone formation was different in FOP vs. control iPS cells. Remarkably, FOP iPS cells showed increased mineralization and enhanced chondrogenesis in vitro. The mineralization phenotypes could be suppressed with a small-molecule inhibitor of BMP signaling, DMH1. Our results indicate that the FOP ACVR1 R206H mutation favors chondrogenesis and increases mineral deposition in vitro. Our findings establish a FOP disease cell model for in vitro experimentation and provide a proof-of-concept for using human iPS cell models to understand human skeletal disorders.
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基因匹配的人类 iPS 细胞表明，软骨和骨分化的倾向因克隆而异，而非细胞来源类型的不同。
影响因子：
3.7
作者：
Nasu A;Ikeya M;Yamamoto T;Watanabe A;Jin Y;Matsumoto Y;Hayakawa K;Amano N;Sato S;Osafune K;Aoyama T;Nakamura T;Kato T;Toguchida J
通讯作者：
Toguchida J
影响因子：
3.7
作者：
Pignolo RJ;Shore EM;Kaplan FS
通讯作者：
Kaplan FS
影响因子：
64.5
作者：
Nakashima, K;Zhou, X;de Crombrugghe, B
通讯作者：
de Crombrugghe, B
影响因子：
4
作者：
Karner, Elerin;Unger, Christian;Wendel, Mikael
通讯作者：
Wendel, Mikael
影响因子：
4.8
作者：
Paine, CT;Paine, ML;Snead, ML
通讯作者：
Snead, ML