iPSC-derived cardiomyocytes reveal abnormal TGF-β signalling in left ventricular non-compaction cardiomyopathy

Kazuki Kodo, Sang Ging Ong, Fereshteh Jahanbani, Vittavat Termglinchan, Keiichi Hirono, Kolsoum Inanloorahatloo, Antje D. Ebert, Praveen Shukla, Oscar J. Abilez, Jared M. Churko, Ioannis Karakikes, Gwanghyun Jung, Fukiko Ichida, Sean M. Wu, Michael P. Snyder, Daniel Bernstein, Joseph C. Wu

研究成果: Article査読

79 被引用数 (Scopus)

抄録

Left ventricular non-compaction (LVNC) is the third most prevalent cardiomyopathy in children and its pathogenesis has been associated with the developmental defect of the embryonic myocardium. We show that patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) generated from LVNC patients carrying a mutation in the cardiac transcription factor TBX20 recapitulate a key aspect of the pathological phenotype at the single-cell level and this was associated with perturbed transforming growth factor beta (TGF-β) signalling. LVNC iPSC-CMs have decreased proliferative capacity due to abnormal activation of TGF-β signalling. TBX20 regulates the expression of TGF-β signalling modifiers including one known to be a genetic cause of LVNC, PRDM16, and genome editing of PRDM16 caused proliferation defects in iPSC-CMs. Inhibition of TGF-β signalling and genome correction of the TBX20 mutation were sufficient to reverse the disease phenotype. Our study demonstrates that iPSC-CMs are a useful tool for the exploration of pathological mechanisms underlying poorly understood cardiomyopathies including LVNC.

本文言語English
ページ(範囲)1031-1042
ページ数12
ジャーナルNature Cell Biology
18
10
DOI
出版ステータスPublished - 2016 9 28
外部発表はい

ASJC Scopus subject areas

  • 細胞生物学

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