Chemical cardiac reprogramming and mechanisms
| Project/Area Number |
17K19678
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| Research Category |
Grant-in-Aid for Challenging Research (Exploratory)
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| Allocation Type | Multi-year Fund |
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| Research Field |
Organ-based internal medicine and related fields
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| Research Institution | University of Tsukuba (2019)
Keio University (2017-2018) |
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Principal Investigator |
Ieda Masaki 筑波大学, 医学医療系, 教授 (70296557)
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| Project Period (FY) |
2017-06-30 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
Fiscal Year 2018: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
Fiscal Year 2017: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
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| Keywords | リプログラミング / 心臓再生 / 化合物 / 内科 / 再生医学 |
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| Outline of Final Research Achievements |
Direct cardiac reprogramming from fibroblasts can be a promising approach for disease modeling, drug screening, and cardiac regeneration in pediatric and adult patients. In this study, we screened 8400 chemical compounds and found that diclofenac sodium (diclofenac), a non-steroidal anti-inflammatory drug, greatly enhanced cardiac reprogramming in combination with Gata4, Mef2c, and Tbx5 (GMT) or GMT plus Hand2. Intriguingly, diclofenac promoted cardiac reprogramming in mouse postnatal and adult tail-tip fibroblasts (TTFs), but not in mouse embryonic fibroblasts (MEFs). Mechanistically, diclofenac enhanced cardiac reprogramming by inhibiting cyclooxygenase-2, prostaglandin E2/ prostaglandin E receptor 4, cyclic AMP/protein kinase A, and interleukin 1β signaling and by silencing inflammatory and fibroblast programs, which were activated in postnatal and adult TTFs.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究で行うケミカルバイロジーは、同定した機能性化合物を基に、心筋リプログラミング誘導薬剤を開発できるのみならず、化合物の標的分子を同定することによって心筋リプログラミングの実行メカニズムを明らかにすることができる。高い心筋誘導効率を示す化合物を発見できれば、心筋リプログラミングに必要な遺伝子を減らして、将来的には薬剤のみで心筋誘導ができるようになる可能性がある。このように本研究は心筋リプログラミングとケミカルバイロジーという共に新しい研究の融合領域を切り拓き、従来の心臓治療に大きな変革や転換を与えうる、独創的かつ革新的な研究である。
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Report
(4 results)
Research Products
(28 results)
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[Journal Article] 2.Tbx6 induces cardiomyocyte proliferation in postnatal and adult mouse hearts.2019
Author(s)
Haginiwa S, Sadahiro T, Kojima H, Isomi M, Tamura F, Kurotsu S, Tani H, Muraoka N, Miyake N, Miyake K, Fukuda K, Ieda M.
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Journal Title
Biochem Biophys Res Commun
Volume: 513
Issue: 4
Pages: 1041-1047
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Tbx6 Induces Nascent Mesoderm from Pluripotent Stem Cells and Temporally Controls Cardiac versus Somite Lineage Diversification.2018
Author(s)
Sadahiro T, Isomi M, Muraoka N, Kojima H, Haginiwa S, Kurotsu S, Tamura F, Tani H, Tohyama S, Fujita J, Miyoshi H, Kawamura Y, Goshima N, Iwasaki YW, Murano K, Saito K, Oda M, Andersen P, Kwon C, Uosaki H, Nishizono H, Fukuda K, Ieda M
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Journal Title
Cell stem cell
Volume: 23(3)
Issue: 3
Pages: 382-395
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Direct In Vivo Reprogramming with Sendai Virus Vectors Improves Cardiac Function after Myocardial Infarction.2018
Author(s)
Miyamoto K, Akiyama M, Tamura F, Isomi M, Yamakawa H, Sadahiro T, Muraoka N, Kojima H, Haginiwa S, Kurotsu S, Tani H, Wang L, Qian L, Inoue M, Ide Y, Kurokawa J, Yamamoto T, Seki T, Aeba R, Yamagishi H, Fukuda K, Ieda M.
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Journal Title
Cell Stem Cell.
Volume: 4
Issue: 1
Pages: 91-103
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Single-Construct Polycistronic Doxycycline-Inducible Vectors Improve Direct Cardiac Reprogramming and Can Be Used to Identify the Critical Timing of Transgene Expression.2017
Author(s)
Umei TC, Yamakawa H, Muraoka N, Sadahiro T, Isomi M, Haginiwa S, Kojima H, Kurotsu S, Tamura F, Osakabe R, Tani H, Nara K, Miyoshi H, Fukuda K, Ieda M.
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Journal Title
Int J Mol Sci.
Volume: 18
Issue: 8
Pages: 1805-1805
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Placental labyrinth formation in mice requires endothelial FLRT2/UNC5B signaling2017
Author(s)
Tai-Nagara Ikue、Yoshikawa Yusuke、Numata Naoko、Ando Tomofumi、Okabe Keisuke、Sugiura Yuki、Ieda Masaki、Takakura Nobuyuki、Nakagawa Osamu、Zhou Bin、Okabayashi Koji、Suematsu Makoto、Kitagawa Yuko、Bastmeyer Martin、Sato Kohji、Klein R?diger、Navankasattusas Sutip、Li Dean Y.、Yamagishi Satoru、Kubota Yoshiaki
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Journal Title
Development
Volume: 144
Pages: 2392-2401
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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