Young at Heart: Pioneering Approaches to Model Nonischaemic Cardiomyopathy with Induced Pluripotent Stem Cells
Table 2
NICMs modelled with patient iPSC-CMs.
NICM
Culture environment
CM disease readouts
Selected interventions (effect)
Reference
Dilated cardiomyopathy
Embryoid bodies (EBs)
Disturbed sarcomeric organisation. ↑Sensitivity to positive inotropic and biomechanical stress (cyclic stretch). ↓Sarcoplasmic reticulum (SR) Ca2+ storage and altered Ca2+ handling. ↓CM contraction forces.
Overexpression of Serca2a (↑[Ca2+]i transients and CM contraction forces). Beta-1-adrenergic blockade (resistance to biomechanical stress and improved myofilament organisation)
CM hypertrophy. Disturbed sarcomeric organisation. ↑Multinucleation. ↑Hypertrophy-related genes. Expression of atrial natriuretic peptide. ↑Beta-/alpha-myosin ratio. Calcineurin activation. NFATc4. ↑Myofibril content. ↑Membrane capacitance. Presence of arrhythmic waveforms. ↑Irregular beating frequencies. CM hypercontractility. Irregular Ca2+ transients. ↓SR Ca2+ release and ↑[Ca2+]i
Blockade of calcineurin-NFAT interaction (40% reduction in CM cell size). Beta-adrenergic stimulation (↑irregular Ca2+ transients and arrhythmia). Coadministration of beta-adrenergic blocker + beta-adrenergic agonist (↓hypertrophy, Ca2+ handling deficiencies, and arrhythmia). Inhibition of Ca2+ influx (eliminated Ca2+ handling abnormalities and arrhythmia, and restoration of normal beating frequency)
↓PKP2 and plakoglobin. ↓Cx43. ↑Maximum width in CM. Disorganised Z-bands. ↑Distorted desmosomes#. Altered lipid droplet morphology. ↑Lipid droplets and accumulation. ↑PPAR-gamma and -alpha. ↑Susceptibility to apoptosis. ↓Beta-catenin. Abnormal [Ca2+]i handling capability. ↓Serca2a and Na+/Ca2+ exchanger 1
Activation of canonical Wnt signalling (↓lipid droplet accumulation). Induction of adult-like energy metabolism and overactivation of PPAR-gamma signalling (increased apoptosis and lipid accumulation). Lentiviral transduction of WT PKP2 (redistribution of plakoglobin to cell membrane and nucleus, ↓apoptosis, and lipogenesis). Scavenging of reactive oxygen species (↓apoptosis). Enrichment for right ventricle-like CMs (↑lipogenesis and apoptosis)
Ma et al. (2013) [122], Caspi et al. (2013) [123], and Kim et al. (2013) [124]
Long QT syndrome 1
EBs
Longer action potentials with slower repolarisation velocities in ventricular- and atrial-like CMs. ↓K+ currents. Translocation of KCNQ1 from the cell surface to the endoplasmic reticulum
Transduction of WT KCNQ1 (redistribution to the cell surface of H9c2 cells). Beta-adrenergic stimulation (impaired rate adaptation of the AP and EADs), rescued by nonselective beta-blockade
↑Field potential durations on microelectrode arrays. Prolonged cardiac repolarisation phase of the AP (ventricular-like CMs).↑Arrhythmogenicity. Presence of EADs. Prolonged [Ca2+]i transients. ↓Densities of rapid delayed potassium channels. ↑Sensitivity to the antiarrhythmic drug, sotalol and the human Ether-à-go-go-related gene (hERG) blocker E-4031. ↑Sensitivity to beta-adrenoreceptor agonism
Lahti et al. (2012) [76], Matsa et al. (2011) [126], and Spencer et al. (2014) [127]
Long QT syndrome 3 (Brugada syndrome)
iPSC coculture with END-2 cells
↓Inward Na+ current density. Defective biophysical properties of Na+ channel. Prolonged inactivation of Nav1.5. Mild prolongation of after-depolarising potential. Altered SR Ca2+ release. DADs and arrhythmias
None
Davis et al. (2012) [128] and Fatima et al. (2013) [129]
Timothy syndrome
EBs
Slower (30 bpm) and more irregular contraction rates. ↓Voltage-dependent inactivation of the L-type Ca2+ channel current. Longer APs (only in ventricular-like CMs). Presence of DADs. Larger and prolonged Ca2+ elevations
Pharmacological ↑ of voltage-dependent inactivation (↓irregular timing and amplitude of Ca2+ transients, and AP duration)
EBs [135]. Directed differentiation method [136, 137]. Staged: days 1–16 EBs + directed differentiation, days 20–24 maturation on hydrogel substrate with a physiological stiffness [138]
↓Dystrophin expression. Abnormal Ca2+ handling. ↓Numbers of spontaneously contracting embryoid bodies and cTnT-positive CMs. ↑Apoptotic markers: Ca2+ overload, mitochondrial damage, caspase-3 activation, and cell death
Beta-adrenergic receptor agonism (↑beating rates). Antisense oligonucleotides exon skipping (exon skipping and dystrophin expression). Minidystrophin gene construct (restored dystrophin expression). Human artificial chromosome carrying the whole dystrophin genomic locus (restored dystrophin expression including multiple isoforms and correct subcellular localisation). Oxidative stress (earlier mitochondrial permeability pore opening). Hypotonic stress (↑susceptibility). Membrane sealing (↓apoptotic markers)
Dick et al. (in press) [136], Guan et al. (2014) [138], Zatti et al. (2014) [137], and Lin et al. (2015) [139]
Or in other cell types where specified. #Desmosomal widening correlated with lipid droplet accumulation.