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タイトル: | Concordant but Varied Phenotypes among Duchenne Muscular Dystrophy Patient-Specific Myoblasts Derived using a Human iPSC-Based Model. |
著者: | IY, Choi H, Lim K, Estrellas J, Mula TV, Cohen Y, Zhang CJ, Donnelly JP, Richard YJ, Kim H, Kim Y, Kazuki M, Oshimura HL, Li A, Hotta J, Rothstein N, Maragakis KR, Wagner G, Lee |
著者名の別形: | 堀田, 秋津 |
発行日: | 7-Jun-2016 |
出版者: | Elsevier |
誌名: | Cell reports |
巻: | 15 |
号: | 10 |
開始ページ: | 2301 |
終了ページ: | 2312 |
抄録: | Duchenne muscular dystrophy (DMD) remains an intractable genetic disease. Althogh there are several animal models of DMD, there is no human cell model that carries patient-specific DYSTROPHIN mutations. Here, we present a human DMD model using human induced pluripotent stem cells (hiPSCs). Our model reveals concordant disease-related phenotypes with patient-dependent variation, which are partially reversed by genetic and pharmacological approaches. Our “chemical-compound-based” strategy successfully directs hiPSCs into expandable myoblasts, which exhibit a myogenic transcriptional program, forming striated contractile myofibers and participating in muscle regeneration in vivo. DMD-hiPSC-derived myoblasts show disease-related phenotypes with patient-to-patient variability, including aberrant expression of inflammation or immune-response genes and collagens, increased BMP/TGFβ signaling, and reduced fusion competence. Furthermore, by genetic correction and pharmacological “dual-SMAD” inhibition, the DMD-hiPSC-derived myoblasts and genetically corrected isogenic myoblasts form “rescued” multi-nucleated myotubes. In conclusion, our findings demonstrate the feasibility of establishing a human “DMD-in-a-dish” model using hiPSC-based disease modeling. |
著作権等: | © 2016 The Author(s). This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
URI: | http://hdl.handle.net/2433/216333 |
DOI(出版社版): | 10.1016/j.celrep.2016.05.016 |
PubMed ID: | 27239027 |
出現コレクション: | 学術雑誌掲載論文等 |
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