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iPSC-derived cardiomyocytes reveal abnormal TGF-ß signalling in left ventricular non-compaction cardiomyopathy. Nature cell biology Kodo, K., Ong, S., 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; 18 (10): 1031-1042

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-ß) signalling. LVNC iPSC-CMs have decreased proliferative capacity due to abnormal activation of TGF-ß signalling. TBX20 regulates the expression of TGF-ß 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-ß 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.

View details for DOI 10.1038/ncb3411

View details for PubMedID 27642787