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

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 was associated with perturbed transforming growth factor beta (TGFβ) signaling. LVNC iPSC-CMs have decreased proliferative capacity due to abnormal activation of TGFβ signaling. TBX20 regulates the expression of TGFβ signaling modifiers including a known genetic cause of LVNC, PRDM16, and genome editing of PRDM16 caused proliferation defects in iPSC-CMs. Inhibition of TGFβ signaling 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.

Modeling Cardiovascular Risks of E-Cigarettes With Human-Induced Pluripotent Stem Cell–Derived Endothelial Cells

“…The iPSCs (over passage 20) from 3 healthy individuals were split at a 1:12 ratio using EDTA as described previously (12), and grown for 3-4 days until they reached ~75% confluence.…”

Left ventricular noncompaction − Risk stratification and genetic consideration −

“…The most common conclusion reached so far is that hyper trabeculation results from altered regulation of cell proliferation, differentiation, and maturation during the formation of the ventricular wall, particularly if the NOTCH signaling pathway is affected. In humans, concern of the NOTCH signaling pathway in pathogenesis of LVNC has been reported [21,32,57,58] (Fig. 3).…”

“…TBX20 regulates the expression of TGF-b signaling 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-b signaling and genome correction of the TBX20 mutation were sufficient to reverse the disease phenotype [58].…”

Force Generation via β-Cardiac Myosin, Titin, and α-Actinin Drives Cardiac Sarcomere Assembly from Cell-Matrix Adhesions

“…Additionally, in the context of understanding human cardiomyopathies, it is attractive to have a human cell model to study the mechanisms of sarcomerogenesis. Advances in genome engineering technologies and induced pluripotent stem cell (iPSC) derived cardiomyocyte differentiation protocols have provided a new source of human cardiomyocytes that have recently been used to model normal cells and various cardiomyopathies in vitro (Birket et al, 2015; Chong et al, 2014; Hinson et al, 2015; Kodo et al, 2016; Lundy et al, 2013; Sun et al, 2012; Wang et al, 2014). These iPSC-derived cardiomyocytes (iPSC-CMs) express a similar RNA profile to that of embryonic day 14.5–18.5 mice, a developmental time when cardiac myofibrillar assembly is most active (DeLaughter et al, 2016; Kuppusamy et al, 2015).…”