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

Research output: Contribution to journalArticle

53 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1031-1042
Number of pages12
JournalNature Cell Biology
Volume18
Issue number10
DOIs
Publication statusPublished - 2016 Sep 28
Externally publishedYes

ASJC Scopus subject areas

  • Cell Biology

Fingerprint Dive into the research topics of 'iPSC-derived cardiomyocytes reveal abnormal TGF-β signalling in left ventricular non-compaction cardiomyopathy'. Together they form a unique fingerprint.

  • Cite this

    Kodo, K., Ong, S. G., Jahanbani, F., Termglinchan, V., Hirono, K., Inanloorahatloo, K., Ebert, A. D., Shukla, P., Abilez, O. J., Churko, J. M., Karakikes, I., Jung, G., Ichida, F., Wu, S. M., Snyder, M. P., Bernstein, D., & Wu, J. C. (2016). iPSC-derived cardiomyocytes reveal abnormal TGF-β signalling in left ventricular non-compaction cardiomyopathy. Nature Cell Biology, 18(10), 1031-1042. https://doi.org/10.1038/ncb3411