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International Journal of Molecular Sciences logoLink to International Journal of Molecular Sciences
. 2019 Sep 6;20(18):4381. doi: 10.3390/ijms20184381

Human Induced Pluripotent Stem-Cell-Derived Cardiomyocytes as Models for Genetic Cardiomyopathies

Andreas Brodehl 1,*, Hans Ebbinghaus 1, Marcus-André Deutsch 2, Jan Gummert 1,2, Anna Gärtner 1, Sandra Ratnavadivel 1, Hendrik Milting 1,*
PMCID: PMC6770343  PMID: 31489928

Abstract

In the last few decades, many pathogenic or likely pathogenic genetic mutations in over hundred different genes have been described for non-ischemic, genetic cardiomyopathies. However, the functional knowledge about most of these mutations is still limited because the generation of adequate animal models is time-consuming and challenging. Therefore, human induced pluripotent stem cells (iPSCs) carrying specific cardiomyopathy-associated mutations are a promising alternative. Since the original discovery that pluripotency can be artificially induced by the expression of different transcription factors, various patient-specific-induced pluripotent stem cell lines have been generated to model non-ischemic, genetic cardiomyopathies in vitro. In this review, we describe the genetic landscape of non-ischemic, genetic cardiomyopathies and give an overview about different human iPSC lines, which have been developed for the disease modeling of inherited cardiomyopathies. We summarize different methods and protocols for the general differentiation of human iPSCs into cardiomyocytes. In addition, we describe methods and technologies to investigate functionally human iPSC-derived cardiomyocytes. Furthermore, we summarize novel genome editing approaches for the genetic manipulation of human iPSCs. This review provides an overview about the genetic landscape of inherited cardiomyopathies with a focus on iPSC technology, which might be of interest for clinicians and basic scientists interested in genetic cardiomyopathies.

Keywords: induced pluripotent stem cells, cardiomyopathies, cardiovascular genetics, cardiomyocytes, ARVC, DCM, HCM, RCM, NCCM, LVNC

1. Introduction

At the beginning of this century, the human genome project was finished [1]. The development of next generation sequencing (NGS) technologies significantly reduced the price and time, allowing for efficient genome and exome analyses, even in clinical routine procedures. However, even 20 years later, the clinical interpretation of genetic sequence variants (GSVs) is still challenging because the functional and structural impact of many variants is unknown. Therefore, multi-disciplinary approaches are often necessary for the interpretation and functional analysis of novel GSVs [2]. At present, in clinical routine procedures, the pathological impact of GSVs is classified due to standards and guidelines of the American College of Medical Genetics and Genomics (ACMG) [3].

Cardiomyopathies are diseases that affect the heart muscle, leading to functional and structural abnormalities [4], and are the main indication for heart transplantation (HTx) [5]. Beside environmental factors, like myocarditis or cardiotoxicity of cancer drugs, non-ischemic cardiomyopathies often have a genetic etiology with dominant inheritance. However, because pathogenic mutations in more than 100 different genes are associated with non-ischemic cardiomyopathies, the interpretation of novel GSVs is still challenging [6]. Moreover, little is currently known on digenic, or even polygenic, etiologies of cardiomyopathies [7]. Incomplete penetrance, different expressivity, and pleiotropy make the clinical interpretation even more challenging.

Functional analyses using adequate cell and animal models can lead to a more sophisticated interpretation of GSVs, which might be not only relevant for genetic counseling but also for the development of personalized therapies. According to the ACMG guidelines, in vitro or/and in vivo functional analyses provide strong criteria (PS3) for the classification of GSVs [3,8]. However, the generation of animal models is still time consuming and expensive. Moreover, in some cases, human cardiomyopathies cannot be modeled using animal models because of species differences. For example, TMEM43-p.S358L is a mutation with full penetrance in several families with arrhythmogenic cardiomyopathy (ACM) [9,10,11]. In contrast, the Tmem43 knock-out, as well as the knock-in mice carrying this specific mutation, do not develop an ACM phenotype [12]. Because of these limitations, human iPSC-derived cardiomyocytes are unprecedented research tools to model and investigate genetic cardiomyopathies.

Here, we provide an overview about the genetic landscape of inherited cardiomyopathies and summarize the development of important human iPSC lines for modelling human cardiomyopathies in vitro. In addition, we review the differentiation into cardiomyocytes and discuss relevant methods used for the cellular and molecular characterization of human iPSC-derived cardiomyocytes.

2. Clinical Background

In clinical cardiology, cardiomyopathies are classified into five major structural subtypes (Figure 1). Dilated cardiomyopathy (DCM, MIM #604145) is mainly characterized by left-ventricular dilation in combination with a decrease of the wall diameter [13]. These structural changes decrease the cardiac ejection fraction. Hypertrophic cardiomyopathy (HCM, MIM #160760) is characterized by the hypertrophy of the ventricular walls and/or the septum [14], leading to a reduced cardiac output. Restrictive cardiomyopathy (RCM, MIM #115210) is caused by an increase in ventricular stiffness, leading to dilated atria and diastolic dysfunction [15]. Hyper-trabeculation of the left ventricular wall is a hallmark for (left-ventricular) non-compaction cardiomyopathy (NCCM, MIM #604169) [16]. It mainly affects the left ventricle, but isolated right ventricular or biventricular forms of NCCM have been reported [17]. Ventricular arrhythmias and predominant right or biventricular dilation are the main clinical symptoms of ACM (MIM #609040) [18]. The fibro fatty replacement of the myocardial tissue is a pathognomonic feature characteristic of ACM [19]. However, at the early stage of the disease, structural changes may be absent or subtle [20]. Because ACM is a progressive disease, left ventricular involvement develops frequently at a later stage [21].

Figure 1.

Figure 1

Schematic overview on cardiomyopathy associated genes and related clinical phenotypes. DCM—Dilated cardiomyopathy. HCM—Hypertrophic cardiomyopathy, ACM—Arrhythmogenic cardiomyopathy, NCCM—Non-compaction cardiomyopathy, RCM—Restrictive cardiomyopathy (Images of the DCM or HCM heart were licensed from shutterstock.com).

3. Genetic Basis of Inherited Cardiomyopathies

Thirty years ago, Seidmans’ group discovered the first pathogenic mutation in MYH7, encoding for β-myosin heavy chain, in a four-generation family, in which several members developed HCM [22]. At present, genetic variants have been described in more than 100 different genes associated with non-ischemic cardiomyopathies or syndromes with cardiac involvement such as Marfan or Leopard syndrome (for an overview, see Table 1). Of note, the spectrum of affected genes and mutations partially overlaps between the different non-ischemic cardiomyopathies (Figure 1). For example, mutations in DES, encoding the muscle specific intermediate filament protein desmin, might cause DCM [23,24], HCM [25], ACM [26,27], RCM [28], or NCCM [29,30,31]. Similarly, mutations in TTN, encoding the giant sarcomere protein titin, can also cause different types of structural, non-ischemic cardiomyopathies [32,33,34]. However, the molecular reasons why mutations in the same gene can cause different cardiac phenotypes are largely unknown.

Table 1.

Overview of cardiomyopathy associated genes carrying mutations.

Gene Protein Function HCM DCM NCCM ACM RCM
ABCC9 ATP Binding Cassette Subfamily C Member 9 ABC transporter [77]
ACAD9 Acyl-CoA Dehydrogenase Member 9 Dehydrogenase [78]
ACADVL Acyl-CoA Dehydrogenase Very Long Chain Dehydrogenase [79]
ACTC1 Cardiac Actin Sarcomere protein [43,80] [81] [82] [83]
ACTN2 α-Actinin 2 Z-band protein [84] [85] [86] [69]
ADRB2 Adrenoreceptor β2 G-protein coupled receptor [87]
AKAP9 A Kinase Anchoring Protein 9 Scaffolding protein [88]
ALMS1 Alstrom Syndrome Protein 1 Microtubule organization [89] 1
ALPK3 α-Kinase 3 Kinase [90] [90]
ANK2 Ankyrin 2 Cytoskeleton linker protein [91] [92]
ANKRD1 Ankyrin Repeat Domain Containing Protein 1 Transcription factor [93] [94,95]
BAG3 Bcl-2 Associated Athanogene 3 Co-chaperone [96] [69,97]
BRAF B-Raf Proto-Oncogene, Serine/Threonine Kinase Kinase [98] 2
C2ORF40 Chromosome 2 Open Reading Frame 40 Hormone [99]
CACNA1C Calcium Voltage-Gated Channel Subunit α1C Calcium channel [100]
CALM3 Calmodulin 3 Calcium binding [101] 3
CALR3 Calreticulin 3 Calcium binding chaperone [46]
CASQ2 Calsequestrin 2 Calcium binding [46]
CASZ1 Castor Zinc Finger 1 Transcription factor [102] [103]
CAV3 Caveolin 3 Scaffolding protein [104]
CAVIN4 Muscle Restricted Coiled Coil Protein Myofibrillar organization [105]
CDH2 N-Cadherin Cell–cell adhesion [106,107]
CHRM2 Cholinergic Receptor Muscarinic 2 G-protein coupled receptor [108]
COL3A1 Collagen Type III Alpha 1 Chain Extra cellular matrix protein [109] 4
COX15 Cytochrome C Oxidase Assembly Homolog COX15 Mitochondrial respiratory chain [110]
CRYAB αB-Crystallin Chaperone-like activity [111] [112]
CSRP3 Muscle LIM Protein Scaffolding protein [113,114,115] [116]
CTF1 Cardiotrophin 1 Cytokine [117]
CTNNA3 αT-Catenin Cell–cell adhesion [118]
DES Desmin Intermediate filament protein [25] [24,119] [30] [26] [28]
DLG1 Discs Large MAGUK Scaffold Protein 1 Scaffolding protein [88]
DMD Dystrophin Dystrophin–glycoprotein complex [120]
DNAJC19 DNAJ Heat Shock Protein Family C19 Co-chaperone [121] [121]
DOLK Dolichol Kinase Phosphorylation of dolichol [122] 5
DPM3 Dolichyl-Phosphate Mannosyltransferase Subunit 3 Mannosyltransferase [123]
DSC2 Desmocollin 2 Cell–cell adhesion [35] [124]
DSG2 Desmoglein 2 Cell–cell adhesion [125] [126,127]
DSP Desmoplakin Cell–cell adhesion [128] [129] [130]
DTNA α-Dystrobrevin Dystrophin-glycoprotein complex [131]
ELAC2 ElaC Ribonuclease Z2 3′-tRNA endoribonuclease [132]
EMD Emerin Nuclear lamina associated protein [133]
EYA4 Eyes Absent Homolog 4 Transcription factor [51]
FBN1 Fibrillin 1 Extra cellular matrix protein [134] 6 [135] 7 [136] 7
FBXO32 F-Box Only Protein 32 Ubiquitin–protein ligase complex [137,138]
FHL1 Four and a Half LIM Domain Protein 1 Scaffolding protein [41]
FHL2 Four and a Half LIM Domain Protein 2 Scaffolding protein [139]
FHOD3 Formin Homology 2 Domain Containing Protein 3 Organization of actin-polymerization [140] [141]
FKRP Fukutin Related Protein Posttranslational modification of dystroglycan [142] 8
FKTN Fukutin Glycosyltransferase of dystroglycan [143]
FLNC Filamin C Cell junction organization [45] [144,145] [145] [72]
FOXD4 Forkhead Box Protein D4 Transcription factor [146]
FXN Frataxin Regulation of mitochondrial iron transport [147] 9
GAA α-Glucosidase Glycogen metabolism [148] 9
GATA4 GATA Binding Protein 4 Transcription factor [149] [150] 10
GATA5 GATA Binding Protein 5 Transcription factor [151]
GATAD1 GATA Zink Finger Domain Containing Protein 1 Gene expression regulation [152]
GLA Galactosidase α Galactose metabolism [153] 11
GTPBP3 GTP Binding Protein 3, Mitochondrial Mitochondrial tRNA modification [154] 12
HAND1 Heart and Neural Crest Derivatives Expressed 1 Transcription factor [155]
HAND2 Heart and Neural Crest Derivatives Expressed 2 Transcription factor [156]
HCN4 Hyperpolarization Activated Cyclic Nucleotide Gated Potassium Channel 4 Potassium channel [157]
HRAS HRas Proto-Oncogene GTPase Signaling protein [158]13
ILK Integrin Linked Kinase Scaffolding protein [159,160] [68]
ISL1 ISL LIM Homeobox 1 Transcription factor [161]
ITGA7 Integrin Subunit A7 Cell–cell and cell–matrix junction protein [162] 14
ITPA Inosine Triphosphate Pyrophosphatase Nucleotide metabolism [163] 15
JPH2 Junctophilin 2 Junctional complex [164] [165]
JUP Plakoglobin Cell–cell adhesion [58]
KCNQ1 Potassium Channel Voltage Gated KQT-Like Subfamily Member 1 Potassium channel [166]
KLHL24 Kelch Like 24 Ubiquitin ligase substrate receptor [167]
LAMA4 Laminin α4 Extra cellular matrix protein [159]
LAMP2 Lysosomal Associated Membrane Protein 2 Chaperone-mediated autophagy [168] 16
LDB3 LIM Domain Binding Protein 3 Z-band protein [169] [170,171] [170,172] [173]
LEMD2 LEM Domain Containing Protein 2 Nuclear lamina associated protein [64,174] 17
LMNA Lamin A/C Nuclear lamina associated protein [49] [175] [63]
LRRC10 Leucine Rich Repeat Containing Protein 10 Actin and α-actinin binding protein [176]
MIB1 Mindbomb Drosophila Homolog 1 Ubiquitin ligase [177]
MIB2 Mindbomb Drosophila Homolog 2 Ubiquitin ligase [178] 18
MRPL3 Mitochondrial Ribosomal Protein L3 Mitochondrial ribosomal protein [179] 19
MRPL44 Mitochondrial Ribosomal Protein L44 Mitochondrial ribosomal protein [180,181]
MYBPC3 Myosin Binding Protein C3 Sarcomere protein [182,183] [184] [185] [186]
MYBPHL Myosin Binding Protein H-Like Sarcomere protein [187]
MYH6 Myosin Heavy Chain 6 Sarcomere protein [188] [188]
MYH7 Myosin Heavy Chain 7 Sarcomere protein [22] [48] [7] [189]
MYH7B Myosin Heavy Chain 7B Sarcomere protein [162] 20
MYL2 Myosin Light Chain 2 Sarcomere protein [190] [191]
MYL3 Myosin Light Chain 3 Sarcomere protein [192] [192]
MYLK3 Myosin Light Chain Kinase 3 Kinase [193]
MYOZ1 Myozenin 1 Calcineurin interacting protein [194]
MYOZ2 Myozenin 2 Calcineurin interacting protein [195]
MYPN Myopalladin Z-band protein [196] [94,197] [196,198]
NCOA6 Nuclear Receptor Coactivator 6 Gene expression regulation [199]
NDUFAF1 NADH: Ubiquinone Oxidoreductase Complex Assembly Factor 1 Mitochondrial respiratory chain [200]
NDUFV2 NADH: Ubiquinone Oxidoreductase Core Subunit V2 Mitochondrial respiratory chain [201,202] 21
NEBL Nebulette Z-band protein [203] [204] [203]
NEXN Nexilin Sarcomere protein [205] [206] [207]
NKX2.5 NK2 Homeobox 5 Transcription factor [208]
OBSCN Obscurin Scaffolding protein [209]
P2RX7 Purinergic receptor P2X7 ATP gated ion channel [210]
PDLIM3 PDZ And LIM Domain 3 Z-band protein [194]
PKP2 Plakophilin 2 Cell-cell adhesion [35] [211] [212]
PLN Phospholamban Regulator of SERCA [46] [213,214] [67]
PPCS Phosphopantothenoylcystein Synthetase Co-enzyme A synthesis [215]
PRDM16 PR Domain Containing Protein 16 Transcription factor [216] [217]
PRKAG2 Protein Kinase AMP Activated Non-catalytic G2 Energy sensor kinase [218,219] 22
PSEN1 Presenilin 1 γ-Secretase [220,221]
PSEN2 Presenilin 2 γ-Secretase [220]
PTEN Phosphatase and Tensin Homolog Phosphatase [150] 23
PTPN11 Protein Tyrosine Phosphatase Non-Receptor Type 1 Phosphatase [222] 24
RAF1 Raf-1 Proto-Oncogene, Serine/Threonine Kinase Kinase [223,224] 25 [225]
RBM20 RNA Binding Protein 20 Splicing factor [52,226] [227] [228,229]
RRAGC Ras Related GTP Binding C GTR/RAG GTP-binding protein [230]
RTKN2 Rhotekin 2 Scaffolding protein [99]
RYR2 Ryanodine Receptor 2 Calcium channel [66]
SCN5A Sodium Channel Voltage Gated Type V Subunit A Sodium channel [50,231] [232]
SCO2 SCO2 Cytochrome C Oxidase Assembly Protein Metallo-chaperone [233]
SDHA Succinate Dehydrogenase Complex Subunit A Mitochondrial respiratory chain [234]
SGCB Sarcoglycan β Dystrophin-glycoprotein complex [235]
SGCD Sarcoglycan δ Dystrophin-glycoprotein complex [236]
SHOC2 Suppressor Of Clear, C. Elegans, Homolog Scaffolding protein [237]
SYNE1 Nesprin 1 Component of the LINC complex [238] [239]
TAZ Tafazzin Cardiolipin metabolism [240] 26 [241,242]
TBX20 T-Box Factor 20 Transcription factor [243,244]
TCAP Thelethonin Titin binding [245] [244,245]
TGFB3 Transforming Growth Factor β3 Growth factor [246]
TJP1 Zonula Occludens 1 Tight junction adapter protein [247]
TMEM43 Transmembrane Protein 43 Nuclear lamina associated protein [9,10]
TMEM87B Transmembrane Protein 87B Endosome-to-trans-Golgi retrograde transport [248]
TNNC1 Cardiac Troponin C Sarcomere protein [39] [249] [250]
TNNI3 Cardiac Troponin I Sarcomere protein [40] [251] [252] [71]
TNNI3K TNNI3 Interacting Kinase Kinase [253]
TNNT2 Cardiac Troponin T Sarcomere protein [38] [254] [255] [83]
TP63 Tumor Protein 63 Transcription factor [256]
TPM1 Tropomyosin 1 Sarcomere protein [38,257] [258] [259] [191]
TRIM63 Tripartite Motif Containing Protein 63 Ubiquitin ligase [260]
TRPM4 Transient Receptor Potential Cation Channel Subfamily M Cation channel [261]
TSFM Mitochondrial Translation Elongation Factor Ts Translation elongation factor [262]
TTN Titin Sarcomere protein [263] [32,264] [87,265] [33] [34]
TTR Transthyretin Carrier protein [266,267] 27
TXNRD2 Thioredoxin Reductase 2 Reduces thioredoxins [268]
VCL Vinculin Cell–cell and cell–matrix junction protein [269,270] [271]
ZBTB17 Zinc Finger and BTB Domain Containing Protein 17 Transcription factor [272,273]

1 Alström syndrome (MIM #203800); 2 Cardiofaciocutaneous syndrome (MIM #115150); 3 Modifier gene; 4 Ehlers–Danlos syndrome (MIM #130090); 5 Multi-organ involvement; 6 Digenetic with PTPN11 mutations, combined with Marfan and Leopard syndrome; 7 Marfan Syndrome (MIM #154700); 8 Limb-girdle muscular dystrophy; 9 Friedreich ataxia (MIM #229300); 10 Digenetic with PTEN; 11 Fabry disease; 12 In combination with lactic acidosis and encephalopathy; 13 Costello syndrome (MIM #218040); 14 Digenetic with MYH7B;15 Martsolf-like syndrome (MIM #212720) in combination with DCM; 16 Danon disease (MIM #300257); 17 In combination with cataract; 18 In combination with giant hypertrophic gastritis (MIM #137280, Ménétrier disease); 18 In combination with psychomotor retardation; 19 Digenetic with ITGA7; 20 In combination with encephalopathy; 21 Wolff–Parkinson–White syndrome (MIM #194200); 22 Digenetic with GATA4 mutation; 23 Noonan syndrome; 24 Noonan syndrome or Leopard syndrome; 25 Barth syndrome (MIM #302060); 26 Amyloid cardiomyopathy (MIM #105210); 27 Fabry disease.

From a genetic point of view, non-ischemic cardiomyopathies are quite heterogeneous [35,36,37]. However, the different non-ischemic cardiomyopathies are characterized by an accumulation of mutations in a distinct set of genes encoding for proteins that are essential for cardiomyocyte function. For example, HCM is mainly caused by mutations in genes encoding sarcomeric proteins such as MYH7 or MYBPC3 (Figure 1). Further mutations in other genes, encoding sarcomere proteins, like TPM1 [38], TNNC1 [39], TNNI3 [40], TNNT2 [38], FHL1 [41,42], or ACTC1 [43], have also been identified in patients with HCM (Table 1). In addition, in rare cases, mutations in genes encoding for Z-disc proteins, like ACTN2 [44] or FLNC [45], or genes encoding for proteins involved in the Ca2+-homeostasis like PLN [46], are also known to cause HCM (see Figure 1).

TTN is the most prevalent DCM-related gene with truncating TTN mutations identified in about 20–25% of DCM patients [32,47]. However, several other genes with a lower prevalence can also cause DCM. Besides, mutations have been identified in genes coding proteins of the sarcomere (e.g., MYH7 [48]), the cytoskeleton (e.g., DES [23,24]), the nuclear lamina (e.g., LMNA [49]), ion channels (e.g., SCN5A [50]), and transcription (e.g., EYA4 [51]) or splicing factors (e.g., RBM20 [52]) (Table 1). RBM20 mutations cause an aggressive early onset phenotype including arrhythmias, sudden cardiac death, and DCM, especially in males [53]. In total, mutations associated with DCM have been described in about 80 different genes (see Figure 1 and Table 1).

NCCM is the third most frequent non-ischemic cardiomyopathy [54,55] and can occur as a primary cardiomyopathy or can be part of a syndromic disease like the Barth syndrome (MIM, #302060) [56]. Mutations in over 20 different genes having a significant overlap with HCM- or DCM-associated genes have been described in NCCM patients so far (see Figure 1 and Table 1). Comparable to HCM, the most prevalent NCCM-associated genes are MYH7 and MYBPC3 [57], which encode sarcomeric proteins (Table 1).

ACM is mainly caused by mutations in genes, encoding structural components of the cardiac desmosomes, and adherens junctions [26,58,59]. The cardiac desmosomes are cell–cell junctions mediating the adhesion of the cardiomyocytes [60]. In about 50% of the ACM patients, one or more mutations in desmosomal genes can be identified [26,59,61] (Table 1). Cardiac desmosomes are linked through the intermediate filaments formed mainly by desmin (DES) with several other cell organelles like the Z-bands or the nuclei. Of note, mutations in the DES gene can also cause ACM by abnormal cytoplasmic desmin aggregation [26,62]. In addition, mutations in genes of the nuclear envelope like LMNA [63], TMEM43 [9,10], or LEMD2 [64] are associated with ACM (Table 1). Furthermore, some rare mutations in non-desmosomal and non-nuclear genes like RYR2 [65,66], PLN [67], or ILK [68] have been identified in ACM patients.

Currently, the genetic etiology of RCM is poorly characterized. Recently, Kostareva et al. and Gallego-Delgado et al. genotyped two small cohorts of unrelated RCM index patients and identified likely pathogenic or pathogenic mutations in 50–75% of them [69,70]. The majority of affected RCM genes, which partially overlap with the group of HCM-associated genes, encode for sarcomere or cytoskeleton proteins (see Figure 1 and Table 1). The first RCM-associated mutation was identified in TNNI3, encoding cardiac troponin I [71]. More recently, there is growing evidence that FLNC mutations, encoding the cytolinker protein filamin-C, are frequently associated with RCM [72,73,74,75,76].

In summary, a relevant amount of all non-ischemic cardiomyopathies have a genetic etiology. Although in most cases, cardiomyopathies are inherited monogenetically, the underlying genetic landscape is complex, diverse, and currently only partially known.

4. Generation of Patient-Specific-Induced Pluripotent Stem Cells Via Reprogramming

In the 1960s, Gurdon et al. cloned Xenopus laevis for the first time [274,275]. Consequently, Gurdon was awarded the Nobel Prize in medicine in 2012, together with Yamanaka [276]. The cloning of mammals by nuclear transfer from somatic cells into enucleated unfertilized mammalian eggs over twenty years ago demonstrated that the cellular differentiation can be artificially turned back into a pluripotent state [277]. The next breakthrough was the identification of essential reprogramming factors by the Yamanaka group [278,279]. Initially, reprogramming was performed with 24 candidate transcription factor genes. Out of these, four critical genes were identified to be crucial for iPSC generation: Sox2, Oct4, Klf4, and c-Myc [278]. Depending on the donor cell type, the set of reprogramming factors can vary since specific cell types might endogenously express some of the necessary factors. For example, c-Myc is not required for the reprogramming of fibroblasts [280].

Different delivery methods were developed for reprogramming of somatic cell types like fibroblasts, lymphocytes, keratinocytes, urine-derived, or intestinal cells into iPSCs (see Figure 2). Initially, iPSCs were generated using retroviral transduction [278,279,281]. The Moloney-based retroviral vector system used by the Yamanaka lab has the advantage of undergoing silencing in the iPSCs state but is restricted to dividing cell types. Therefore, lentiviruses were used to improve the transduction efficiency of dividing and non-dividing cell types. However, after lentiviral transduction, the expression of the reprogramming factors are poorly silenced [282,283], leading to difficult differentiation of these iPSCs [284]. Therefore, inducible systems were used, allowing for the silencing of the Yamanaka factors in iPSCs [284,285].

Figure 2.

Figure 2

Schematic overview about different delivery methods of the Yamanaka factors into somatic primary cells for reprogramming (sub-figures for the cell types and viruses were licensed from shutterstock.com).

However, usage of integrating viral systems enhances the risk for insertional mutagenesis, limiting their application [286]. Furthermore, the transgene reactivation of c-Myc showed increased tumorigenicity in chimeric mice [280], limiting the usage of iPSCs for clinical approaches. To overcome these limitations, non-integrating delivery methods have been developed. Transient transfection of the PiggyBac transposon with a Cre-mediated excisable system was one of the first non-integrating methods (Figure 2). Minimized genome modification, in combination with silencing of the reprogramming factor expression in the iPSC state, are the main advantages of this system [287]. Another approach is the adenoviral transduction leading to an overexpression of the reprogramming factors in the host cells without genomic integration [288]. Transient transfection or electroporation with episomal plasmids encoding the reprogramming factors is an alternative method to produce virus-free iPSCs [289] (Figure 2). However, the efficiency of this delivery method is quite low [290]. More promising non-inserting delivery methods include the use of Sendai viruses [291], which are RNA viruses that do not enter the nucleus, thereby decreasing the risk of genomic insertion.

Reprogramming using miRNAs that are specifically expressed in embryonic pluripotent stem cells (ESCs) can enhance the reprogramming efficiency [292]. For example, the miR302/367 cluster is highly expressed in pluripotent cells, but not in differentiated cells, and its promoter is transcriptionally regulated by the reprogramming factors Oct4 and Sox2 [293]. This cluster is functionally involved in regulation of the cell cycle and maintenance of pluripotency. Overexpression of the miRNA cluster miR302/367 can promote the reprogramming of somatic cells [294]. In combination with the reprogramming factors, a higher efficiency can be achieved [292]. Although RNA-based reprogramming methods show higher efficiency compared to Sendai virus and episomal methods, the reliability is significantly lower [295]. Non-integrating delivery methods provide iPSCs that are more applicable for clinical disease modeling. Besides the integrating and non-integrating delivery systems, DNA-free approaches with transgene free reprogramming have been established. Small compounds or recombinant reprogramming factors were used (Figure 2) [296,297]. For example, the histone deacetylase inhibitor valproic acid improves the reprogramming efficiency [298,299]. The efficient synthesis of large amounts of purified native recombinant proteins and the permeabilization of the plasma membranes are crucial for this reprogramming method [300]. More recently, the CRISPR-dCas9-based synergistic activation mediator (SAM) system has been developed and applied for reprogramming [301,302]. This system is based on a fusion protein of the enzymatic inactive form of Cas9 (dCas9) and a transcription activator domain forming an artificial transcription factor which, in combination with specific guide RNAs, is able to activate the transcription of endogenous genes with minimal off-target activity. Weltner et al. successfully used this system for the expression of different reprogramming factors to generate iPSCs [302].

In summary, different integrating and non-integrating approaches have been developed for reprogramming different cell types into iPSCs to improve the efficiency and to reduce the risk of further genomic alterations (see Figure 2).

5. Genetic Modification of Induced Pluripotent Stem Cell Lines

Besides the generation of human iPSCs from the primary cells of mutation carriers by direct reprogramming [278,281], specific genetic mutations can also be inserted using genome editing techniques like clustered regularly interspaced short palindromic repeats associated protein 9 (CRISPR-Cas9) [303], CPF1 [304], or transcription activator-like effector nucleases (TALENs) [305,306]. In addition to genome editing approaches, iPSCs or the differentiated cardiomyocytes can be genetically modified by overexpressing specific mutant proteins [307,308] or by decreasing the expression of specific mutant proteins, e.g., by RNA interference [309].

Using patient-derived iPSCs, it is sometimes challenging to correlate directly functional effects in vitro with the specific genetic variants because the genetic and epigenetic background of the cells is largely unknown [310]. In contrast to patient-derived iPSCs, which carry the sum of all genetic sequence variants of the affected patients, genome edited iPSC lines carry specifically inserted mutations. Therefore, the effects of particular mutations can be directly compared with their corresponding isogenic wild-type controls in genome-edited iPSCs.

Genome editing techniques like CRISPR-Cas9 are based on endonuclease activity, which insert double-strand breaks (DSBs) into the DNA double helix at specific sites. Different endogenous cellular repair mechanisms like non-homologous end joining (NHEJ) or homology directed repair (HDR) are used for the repair of these DSBs. However, NHEJ is an imprecise process, which might lead to the insertion, deletion, or substitution of nucleotides [311]. Indel variants frequently cause frameshifts, and consequently, premature termination codons (PTCs). PTCs are recognized by nonsense mediated RNA decay (NMD) degrading the mutant mRNA. Therefore, DSBs can be efficiently used to generate knock-out models. In contrast, HDR uses DNA template molecules for the specific repair of the DSBs. In combination with suitable donor molecules, e.g., single-stranded oligonucleotides or double-stranded DNA templates like PCR products or plasmids, HDR can be used to insert specific point mutations [312], small peptide-encoding tags [313], or even larger fluorescence proteins at specific positions [314,315,316]. Unfortunately, the ratio of HDR to NHEJ is low, limiting the efficiency of knock-in strategies [317]. Therefore, different approaches for inhibiting NHEJ or promoting HDR have been developed (for reviews, see References [317,318,319]). The delivery of donor template molecules in close proximity to the DSBs by coupling Cas9 with the donor molecule might be a promising strategy [320,321,322]. An alternative are dCas9-related base pair editors [323,324,325], which can be used to exchange relevant nucleotides at specific positions.

6. Differentiation of Human Induced Pluripotent Stem Cells into Cardiomyocytes

The human adult heart is a post-mitotic organ with a very limited capacity for regeneration [326]. Beside the murine, atrial cardiomyocytes-related HL-1 cell line [327], no further contracting human cardiomyocytes cell lines are therefore currently available. Because of ethical and technical issues, the isolation of primary human cardiomyocytes from human surgical material and their long-time culture is in most cases impossible. Primary cardiomyocytes isolated from rodent hearts have characteristic differences like a different electrophysiology in comparison to the human ones. Therefore, cardiomyocytes derived from human ESCs or iPSCs are the predominant human cell resource [328,329].

Originally, Zhang et al. described the differentiation of cardiomyocytes from human iPSCs [330]. Comparable to ESCs, human iPSCs form embryonic bodies in suspension that can be further differentiated into cardiomyocytes [330,331,332,333,334]. However, the efficiency of this process was limited. In addition, monolayers of iPSC-derived cardiomyocytes can be generated [335,336]. In vivo, cardiogenesis is a complex cellular and molecular process where different transcription factors, growth factors, and miRNAs are time dependently expressed and regulated [337,338,339,340,341]. Driven by discoveries from development biology, it has been recognized that different recombinant growth factors, e.g., BMP4, can also be used to increase the efficiency of in vitro differentiation into cardiomyocytes [342,343,344]. In addition, modulation of the Wnt pathway by small molecules, e.g., CHIR99021 and IWP2, efficiently increases the differentiation into cardiomyocytes about 90% [344,345]. Furthermore, metabolic selection by glucose depletion, in combination with lactate supplementation, can be applied for further accumulation of cardiomyocytes [346,347]. Recently, Zhao et al. developed a method for the differentiation and generation of heteropolar cardiac tissue with atrial and ventricular ends [348]. Talkhabi et al. has previously reviewed the differentiation of iPSCs into cardiomyocytes in detail [349].

7. Methods for the Functional Analysis of Cardiomyocytes Derived from Induced Pluripotent Stem Cells

Besides general histochemical or molecular methods, e.g., RNA-Seq or proteomics, specific techniques for the functional in vitro analysis of the electrophysiological and contractile properties of iPSC-derived cardiomyocytes are frequently used. Patch clamping and multiple electron arrays (MEAs) are frequently used for the electrophysiological analysis of iPSC-derived cardiomyocyte monolayers [350,351]. The application of Ca2+ specific fluorescence dyes, e.g., Indo1 or Fura-2, allows for the microscopic analysis of Ca2+ transients [352,353,354]. Additionally, voltage-sensitive fluorescence dyes like di-4-ANEPPS can be used for the analysis of the electrophysiological properties [355]. For the analysis of the contractile properties of iPSC-derived cardiomyocytes, microscopic techniques like traction force measurements have also been used [356]. Atomic force microscopy can also be applied for measuring the contraction forces of iPSC-derived cardiomyocytes [357,358]. Feaster and coworkers developed a method to culture iPSC-derived cardiomyocytes on Matrigel mattresses, allowing for the contractility measurement by cell shortening [359].

8. Overview about Existing iPSC Lines Carrying Cardiomyopathy Associated Mutations

In 2010, Carvajal-Vergara and co-workers published a landmark paper about the generation of an iPSC line carrying the heterozygous mutation PTPN11-p.T468M [360]. Mutations in PTPN11 cause the Leopard syndrome [361,362], which is frequently associated with severe HCM [363]. Interestingly, these iPSC-derived cardiomyocytes were larger and presented an abnormal, nuclear localization of NFATc4 [360]. Members of the NFAT family are involved in the calcineurin-NFAT signaling regulating hypertrophy [364]. Since this original report, about 70 different iPSC lines carrying cardiomyopathy-associated mutations in several different genes have been generated (Table 2). The majority of these mutant iPSC lines have been used for phenotypic modeling of genetic cardiomyopathies using electrophysiological and/or contraction measurements (Table 2). Besides modeling genetic cardiomyopathies, iPSC-derived cardiomyocytes were also used for the modeling of non-genetic causes of cardiomyopathies, e.g., doxorubicin cardiotoxicity [263,365], hypoxia [366], peripartum [367], or diabetic cardiomyopathy [368,369,370,371], or even infection with Trypanosoma cruzi [372] or with coxsackievirus B3 [373].

Table 2.

Overview about important iPSC lines carrying mutations in genes associated with genetic cardiomyopathies or related diseases.

Gene Protein Mutation(s) Method of Generation Main Phenotypic Findings Associated Disease References
ACTC1 Cardiac Actin p.E99K
  • Sendai virus transduction

  • Isogenic controls using CRISPR-Cas9 (PiggyBac)

Arrhythmias HCM/LVNC [380]
ALPK3 α-Kinase 3 p.W1264Xhom Electroporation with episomal plasmids
  • Sarcomeric disarray

  • Ca2+ handling defects

HCM [381]
BAG3 Bcl-2 Associated Athanogene 3
  • p.R90X

  • p.R90Xhom

  • p.R123X

  • Electroporation with episomal plasmids

  • & genome editing using

  • CRISPR-Cas9

  • TALENs

  • Decreased BAG3 expression

  • Sarcomeric disarray after prolonged culture

  • Decreased contraction

DCM [374]
BRAF B-Raf Proto-Oncogene, Serine/Threonine Kinase
  • p.Q257R

  • p.T599R

  • Retroviral transduction

  • Electroporation with episomal plasmids

  • Cellular hypertrophy

  • Pro-hypertrophic gene expression

  • Ca2+ handling defects

  • Abnormal TGFβ signaling

CFCS/HCM [382]
CAV Caveolin
  • c.303G > C

  • c.233C > A

  • c.∆184-192

Electroporation with episomal plasmids NA MP [383]
CRYAB αB-Crystallin
  • c.343delThet

  • c.343delThom

Retroviral transduction and genome editing (zinc finger nucleases)
  • No detectable expression of mutant αB-Crystallin

  • Loss of function mechanism

MFM [384]
DES Desmin p.N116S Lentiviral transduction NA ACM [385]
DES Desmin c.735+1G > A Sendai virus transduction NA DRC [386]
DES Desmin p.A285V Retroviral transduction
  • Desmin aggregation

  • Z-disk streaming

  • Decreased spontaneous beating rate

DCM [387]
DMD Dystrophin
  • ∆Ex8-12

  • c.5899C > T

Sendai virus transduction
  • Electrophysiological alterations

  • Arrhythmias

  • Prolonged action potential

DMD [388]
DMD Dystrophin
  • ∆Ex8-9

  • ∆Ex6-9

  • ∆Ex7-11

  • ∆Ex3-9

Sendai virus transduction in combination with CRISPR-Cas9
  • Out of frame deletion ∆Ex8-9 reduce contraction force

  • Second deletions to correct the reading fame of DMD restores the contractility

DMD [379]
DMD Dystrophin
  • c.263delG

  • ∆Ex50

Lentiviral transduction
CRISPR-Cas9
  • Reduced contractility

  • Ca2+ handling defects

DMD [389,390]
DSG2 Desmoglein-2 p.G638R Sendai virus transduction
  • Electrophysiological alterations

  • Ion channel dysfunction

ACM [391]
DSP Desmoplakin p.R451G Sendai virus transduction & genome editing for correction (CRISPR-Cas9) Reduced desmoplakin expression ACM [392]
FBN1 Fibrillin 1 c.4028G > A Sendai virus transduction NA Marfan Syndrome (HCM) [393]
FKRP Fukutin Related Protein c.826C > Ahom Lentiviral transduction
  • Abnormal action potential

  • Electrophysiological alterations

  • Decreased expression of SCN5A and CACNA1C

Limb-Girdle Muscular Dystrophy (DCM) [394]
FXN Frataxin Expanded GAA repeats Retroviral transduction
  • Iron homeostasis defects

  • Disorganized mitochondria

  • Cellular hypertrophy

  • Increased BNP expression

  • Ca2+ handling defects

Friedreich Ataxia (HCM) [395]
FXN Frataxin Expanded GAA repeats
  • 800/600

  • 900/400

Lentiviral transduction
  • Impaired mitochondrial function

  • Decreased mitochondrial membrane potential

  • Degeneration of mitochondria

Friedreich Ataxia (HCM) [396]
GLA Galactosidase α IVS4+919G > A Retroviral transduction
  • Decreased α-galactosidase activity

  • Cellular hypertrophy

  • Upregulation of fibrotic genes

Fabry Disease (HCM) [397,398]
LAMP2 Lysosomal Associated Membrane Protein 2 IVS6+1_4delGTGA Sendai virus transduction Autophagy dysfunction Danon Disease (CM) [399]
LAMP2 Lysosomal Associated Membrane Protein 2
  • c.129-130insAT

  • IVS-1.c64+1G > A

Unknown
  • Mitochondrial-oxidative stress

  • Apoptosis

  • Disrupted mitophagic flux

  • Mitochondrial respiratory deficiency

Danon Disease (CM) [400]
LAMP2 Lysosomal Associated Membrane Protein 2
  • c.1082delA

  • c.247C > T

  • c.64+1G > A

  • Retroviral transduction

  • Sendai virus transduction

  • CRISPR-Cas9 for correction

  • Defects in autophagic fusion

  • Mitochondrial abnormalities

  • Contractile abnormalities

Danon Disease (CM) [401]
LMNA Lamin A/C p.S143P Sendai virus transduction
  • Sarcomere damage after hypoxia

  • Arrhythmias after β-adrenergic stimulation

  • Ca2+ handling defects

DCM [402]
LMNA Lamin A/C p.S18fsX Combined lentiviral and retroviral transduction Normal nuclear membrane morphology DCM [403]
LMNA Lamin A/C p.R225X Lentiviral transduction
  • Reduced expression of lamin A/C

  • Increased cellular apoptosis under electrical stimulation

DCM [404]
LMNA Lamin A/C
  • p.R225X

  • p.Q354X

  • p.T518fsX29

Lentiviral transduction
  • Increased nuclear blebbing under electrical stimulation

  • Increased apoptosis under electrical stimulation

  • Haploinsufficiency

  • Treatment with PTC124 reverse the phenotypic findings

DCM & conduction disorders [405]
LMNA Lamin A/C p.K219T Lentiviral transduction
  • Electrophysiological alterations

  • Downregulation of SCN5A expression by epigenetic modulation of the promoter

DCM & conduction disorders [406]
MT-RNR2 Mitochondrially Encoded 16S rRNA m.2336T > C Retroviral transduction
  • Decreased stability of 16S rRNA

  • Mitochondrial dysfunction

  • Reduced ATP/ADP ratio

  • Reduced mitochondrial potential

  • Electrophysiological alterations

HCM [407]
MYBPC3 Myosin Binding Protein C3
  • p.V321M

  • p.V219L

  • c.2905+1G > A

Sendai virus transduction Abnormal Ca2+ handling HCM [408]
MYBPC3 Myosin Binding Protein C3 p.R326Q Electroporation with episomal plasmids Ca2+ handling deficits HCM [409]
MYBPC3 Myosin Binding Protein C3 c.2373 Lentiviral transduction
  • Cellular hypertrophy

  • Contractile defect

HCM [410,411]
MYBPC3 Myosin Binding Protein C3 p.R502W Electroporation with episomal plasmids NA HCM [412]
MYBPC3 Myosin Binding Protein C3
  • p.R502W

  • p.W792VfsX41

CRISPR-Cas9
  • Hypercontractility

  • P53 activation

  • Oxidative stress

  • Metabolic stress

HCM [413]
MYBPC3 Myosin Binding Protein C3
  • p.R943X

  • p.R1073fsX4

Sendai virus transduction & genome editing for correction (CRISPR-Cas9)
  • Reduced expression of MYBPC3 at the mRNA level but not at the protein level

  • Ca2+ handling defects

  • Activation of nonsense-mediated mRNA decay

HCM [414,415]
MYBPC3 Myosin Binding Protein C3 p.G999-Q1004del Sendai virus transduction
  • Cellular hypertrophy

  • Myofibrillar disarray

  • Reduced MYBPC3 expression

  • Increased ANP expression

HCM [416]
MYBPC3 Myosin Binding Protein C3 p.Q1061X
  • Sendai virus transduction

  • Retroviral transduction

Arrhythmias HCM [417,418]
MYBPC3 Myosin Binding Protein C3 p.V454CfsX21 Retroviral transduction
  • Haploinsufficiency (at the mRNA and protein level)

  • Cellular hypertrophy

  • Altered gene expression

  • Efficient gene replacement using AAV9 reduce phenotypic findings

HCM [419]
MYBPC3 Myosin Binding Protein C3 ∆25 bp in intron 32 including the splicing branch point & p.D389V (same allele) Sendai virus transduction
  • Cellular hypertrophy

  • Ca2+ handling deficits

HCM [420]
MYBPHL Myosin Binding Protein H-Like p.R255X Electroporation with episomal plasmids Haploinsufficiency by nonsense mediated mRNA decay DCM & conduction disorders [187]
MYH7 Myosin Heavy Chain 7 p.R663H Sendai virus transduction Abnormal Ca2+ handling HCM [408]
MYH7 Myosin Heavy Chain 7
  • p.R453Chet

  • p.R453Chom

CRISPR-Cas9
  • Cellular hypertrophy

  • Sarcomeric disarray

  • Increased expression of hypertrophy markers

  • Ca2+ handling deficits

HCM [421]
MYH7 Myosin Heavy Chain 7
  • p.R403Q

  • p.V606M

CRISPR-Cas9
  • Hypercontractility

  • P53 activation

  • Oxidative stress

  • Metabolic stress

HCM [413]
MYH7 Myosin Heavy Chain 7 p.V698A Electroporation with episomal plasmids NA HCM [422]
MYH7 Myosin Heavy Chain 7 p.E848G Electroporation with episomal plasmids Reduced contractile function HCM [423,424]
MYH7 Myosin Heavy Chain 7 p.R403Q Electroporation with episomal plasmids NA HCM [425]
MYH7 Myosin Heavy Chain 7 p.R633H Lentiviral transduction
  • Ca2+ handling deficits

  • Arrhythmias

  • Cellular hypertrophy

HCM [414,426]
MYH7 Myosin Heavy Chain 7 p.R442G Retroviral transduction
  • Disorganized sarcomeres

  • Increased expression of genes involved in cell proliferation

  • Electrophysiological alterations

HCM [427]
MYL2 Myosin Light Chain 2 p.R58Q Non-integrating mRNA/miRNA technology
  • Cellular hypertrophy

  • Myofibrillar disarray

  • Irregular contraction

  • Decreased Ca2+ transients

HCM [428]
MYL3 Myosin Light Chain 3
  • p.A57Dhet

  • p.A57Dhom

  • p.A57Ghet

CRISPR-Cas9
  • Asymptomatic

  • Classification of benign GSVs

HCM [375]
PKP2 Plakophilin-2 p.L614P Retroviral transduction
  • Reduced expression of plakophilin-2

  • Adipogenic phenotype

ACM [429]
PKP2 Plakophilin-2
  • c.2484C > Thom

  • c.2013delC

Retroviral transduction
  • Lipogenesis

  • Apoptosis

  • Ca2+ handling deficits

  • Pro-fibrotic gene expression

  • Dysregulation of genes, encoding cell-cell connections.

ACM [430,431,432]
PKP2 Plakophilin-2 c.972insT Retroviral transduction
  • Reduced expression of plakophilin-2

  • Changes of the desmosomal structure

  • Lipid droplet accumulation

ACM [433]
PKP2 Plakophilin-2
  • c.354delT

  • p.K859R

Sendai virus transduction NA ACM [434]
PKP2 Plakophilin-2 c.2569_3018del50 Electroporation with episomal plasmids NA ACM [435]
PLN Phospholamban p.R9C CRISPR-Cas9
  • Cellular hypertrophy

  • Ca2+ handling deficits

  • Increased expression of hypertrophic markers

  • Altered metabolic state

  • Changes of miRNA expression

  • Increased expression of profibrotic genes

DCM [414,436]
PLN Phospholamban p.R14del Transfection with mRNAs& genome editing (TALENs) for mutation correction
  • Ca2+ handling deficits

  • Abnormal cytoplasmic localization of phospholamban

  • Increased expression of hypertrophic markers

  • Gene correction reverses the phenotypic findings

DCM [437,438]
PRGAG2 Protein Kinase AMP-Activated Non-Catalytic Subunit Gamma 2 p.R302Q Sendai virus transduction & genome editing for correction (CRISPR-Cas9)
  • Arrhythmias

  • Electrophysiological alterations

  • Cellular hypertrophy

  • Gene correction using CRISPR-Cas9 reverses the phenotypic findings

Wolff–Parkinson–White Syndrome (HCM) [439]
PRKAG2 Protein Kinase AMP-Activated Non-Catalytic Subunit Gamma 2 p.N488I Lentiviral transduction & genome editing for correction (TALEN)
  • Activated AMPK remodeled metabolism

  • Cellular hypertrophy

HCM [440]
PTPN11 Protein Tyrosine Phosphatase Non-Receptor Type 11 p.T468M Retroviral transduction
  • Cellular hypertrophy

  • Impaired sarcomere structure

LEOPARD Syndrome (HCM) [360]
PTPN11 Protein Tyrosine Phosphatase Non-Receptor Type 11 p.Q510P Sendai virus transduction NA LEOPARD Syndrome (HCM) [441]
RAF1 Raf-1 Proto-Oncogene, Serine/Threonine Kinase p.S257L Electroporation of episomal plasmids & genome editing for correction (CRISPR-Cas9)
  • Cellular hypertrophy

  • Myofibrillar disarray

  • Hyperactivation of MEK1/2 pathway

  • Increased ERK5 signaling

Noonan Syndrome (HCM) [442]
RBM20 RNA Binding Motif Protein 20 p.S635A Lentiviral transduction
  • Altered Ca2+ handling

  • Impaired sarcomere structure

  • Reduced titin N2B isoform expression

DCM [443]
RBM20 RNA Binding Motif Protein 20 p.R636S Sendai virus transduction
  • Impaired sarcomere structure

  • Altered transcriptome

  • Altered Ca2+ handling

  • Apoptotic changes

  • Therapeutic treatment using β-blockers or Ca2+ channel blockers reverse phenotypic findings

DCM [444,445]
RYR2 Ryanodine Receptor 2 p.F2483I Retroviral transduction
  • Arrhythmias

  • Altered Ca2+ handling

CPVT [350]
RYR2 Ryanodine Receptor 2
  • p.S404R & p.N685S

  • p.G3946S & p.G1885E

Sendai virus transduction
  • Altered Ca2+ handling

  • Calmodulin-dependent protein kinase II inhibition reverse the arrhythmias

CPVT [376]
SCN5A Sodium Voltage-Gated Channel Alpha Subunit 5
  • p.S1898R

Sendai virus transduction & CRISPR-Cas9 for correction
  • Reduction in peak sodium channel

ACM [446]
SCN5A Sodium Voltage-Gated Channel Alpha Subunit 5 p.R219H Sendai virus transduction
  • Proton leakage

  • Disrupted ion homeostasis

  • Structural abnormalities

  • Electrophysiological alterations

  • Reduced contraction

ACM/DCM [447]
SCO2 SCO2 Cytochrome C Oxidase Assembly Protein
  • p.E140K

  • p.G193Shom

Sendai virus transduction
  • Structural abnormalities

  • Altered Ca2+ handling

HCM [448]
TAZ Tafazzin
  • c.517delG

  • c.328T > C

Transfection with synthetic mRNAs & CRISPR-Cas9 for correction
  • Impaired sarcomere structure

  • Decreased contraction

  • Increased reactive oxygen species

Barth Syndrome [449]
TBX20 T-Box Factor 20
  • p.T262M

  • p.Y317X

Sendai virus transduction
  • Perturbed TGFβ signaling

  • Reduced expression of cardiac transcription factors

LVNC [450]
TNNT2 Cardiac Troponin T p.R92W Sendai virus transduction & CRISPR-Cas9 for correction Abnormal Ca2+ handling HCM [408]
TNNT2 Cardiac Troponin T p.R173W Lentiviral transduction
  • Decreased contractility

  • Altered Ca2+ handling

  • Impaired sarcomere structure

DCM [414,451,452,453,454]
TNNT2 Cardiac Troponin T
  • Compound heterozygous: ∆5bp and ∆2bp deletions in exon 2 leading to frameshifts

  • Heterozygous ∆27bp deletion in exon 2 leading to a frameshift

TALEN
  • Sarcomere disassembly

  • Altered Ca2+ handling

DCM/HCM [453]
TNNT2 Cardiac Troponin T p.I79N CRISPR-Cas9
  • Impaired sarcomere structure

  • Increased systolic function

  • Impaired relaxation

  • Altered Ca2+ handling

HCM [455,456]
TPM1 Tropomyosin-1 p.D175N
  • Sendai virus transduction

  • Retroviral transduction

Arrhythmias HCM [417,418]
TTN Titin
  • p.W976R+/-

  • p.V6382fs+/-

  • p.V6382fs-/-

  • p.A22352fs+/-

  • p.P22582fs+/-

  • p.N22577fs+/-

  • p.N22577fs-/-

  • p.T33520fs-/-

  • Lentiviral transduction (for patient specific iPSC)

  • CRISPR-Cas9 (for generation of isogenic iPSC)

  • Impaired sarcomere structure

  • Decreased contractility

  • Diminished activation of growth factors, hypoxia regulating factors and MAP kinases

DCM [457]
TTN Titin p.S14450fsX4 Sendai virus transduction Antisense-mediated exon skipping restores titin expression DCM [377]
TTN Titin
  • c.86076dupA

  • c.70690dupAT

Lentiviral transduction
  • Sarcomere defects

  • Diminished inotropic and lusitropic responses

DCM [458]
TTR Transthyretin p.L55P Lentiviral transduction Increased oxidative stress Hereditary Transthyretin Amyloidosis [459]

ACM—Arrhythmogenic cardiomyopathy; CFCS—Cardio facio cutaneous syndrome; CM—Cardiomyopathy; CPVT—Catecholaminergic polymorphic ventricular tachycardia; DCM—Dilated cardiomyopathy; DMD—Duchenne muscular dystrophy; DRC—Desmin-related cardiomyopathy; HCM—Hypertrophic cardiomyopathy; LVNC—Left-ventricular non-compaction cardiomyopathy; MFM—Myofibrillar myopathy; MP—Myopathy; NA—Not assessed; RCM—Restrictive cardiomyopathy.

In the beginning, iPSC lines generated from healthy probands were frequently used as controls for experiments. However, because different iPSC lines have a variable genetic background, this approach has limitations. Since the development of efficient genome editing technologies like CRISPR-Cas9 or TALENs [303], it is common to generate isogenic control lines [374]. Interestingly, the reverse approach by inserting specific mutations in iPSCs from healthy control persons is also sometimes used [375]. In some cases, the rationale of these studies is the functional characterization of specific cardiomyopathy-associated mutations, which might contribute to a pathogenicity classification. In addition, iPSC-derived cardiomyocytes were used for the development of therapeutic strategies, e.g., genome editing. An interesting application of iPSC-derived cardiomyocytes is the testing of specific gene therapeutic concepts [376]. For example, Gramlich et al. applied antisense-mediated exon skipping in iPSC-derived cardiomyocytes with a truncating TTN (TTNtv) mutation for restoring the expression of titin [377]. However, at present, it appears that some of the TTNtv do not lead to premature translation termination in failing human hearts [378]. Thus, iPSCs might therefore be useful in future to check and modulate possible read-throughs of TTNtv mutations as well. Similarly, Kyrychenko et al. used CRISPR-Cas9 to delete whole exons within the DMD gene to correct the reading frame [379]. Of note, this strategy restores contractility in the iPSC-derived cardiomyocytes [379]. Hopefully, the combination of iPSC-derived cardiomyocytes with adequate modern genetic engineering tools will contribute in future to the development of therapeutic options in the context of personalized medicine.

9. Limitations of Human Induced Pluripotent Stem-Cell-Derived Cardiomyocytes

Besides cardiomyocytes, the human adult heart consists of several different cell types like fibroblasts, endothelial cells, leukocytes, pericytes, and smooth muscle cells. It has been estimated that the proportion of cardiomyocytes in myocardial tissue is around 25–35%, indicating that the majority of the cardiac cells are non-cardiomyocytes [460]. However, the molecular and cellular interactions and interferences between the different cardiac cell types are poorly understood. In particular, under pathological conditions like inflammation or fibrosis, the cellular composition of the heart of cardiomyopathy patients can vary and might change over time. Therefore, it is in general challenging to model the complex cellular and molecular networks using iPSC-derived cardiomyocytes in vitro, although the artificial generation of cardiac tissue has been impressively improved during the last few years [461,462,463,464,465]. Besides these general limitations, iPSCs and iPSC-derived cardiomyocytes have some specific limitations, which are outlined in the following paragraphs.

9.1. Genomic Instability

Genomic instability of iPSCs can be a fundamental problem limiting the clinical application of iPSC-derived cells because of safety concerns [466]. Mayshar et al. showed that a significant portion of iPSC and ESC lines carry full or partial chromosomal aberrations [467]. However, even for in vitro analysis, genomic instability could be an important issue, especially in the context of modeling genetic diseases like cardiomyopathies. Therefore, novel iPSC lines should be genetically characterized in general. Karyotype analysis using Giemsa staining or comparative genomic hybridization arrays can be used to detect larger chromosomal abnormalities, while next generation sequencing assays can be applied for genetic analysis at the single nucleotide level.

Three different mechanisms contribute to the mutagenesis in iPSCs: besides the existence of genetic variants in the parental somatic donor cells, mutations can be introduced during reprogramming procedure or during the long-time culture of iPSCs [468]. Of note, mutations might accumulate in iPSCs over the culturing time [469]. Therefore, it is advisable to use early passages and to repeat analyses for genetic stability from time to time.

9.2. Heterogeneity of iPSC-Derived Cardiomyocytes

Although cardiac differentiation protocols for iPSCs have been improved significantly over recent years [345,470], it should be kept in mind that iPSC-derived cardiomyocytes are still a heterogeneous cell population. Especially for bulk down-stream applications like proteomics, genomics, or metabolomics, this might have a significant impact.

9.3. Cellular, Molecular, and Functional Differences of Adult Ventricular Cardiomyocytes and iPSC-Derived Cardiomyocytes

Even though human iPSC-derived cardiomyocytes are contractile cell types, there are important cellular, molecular, and functional differences compared to adult cardiomyocytes. The most obvious differences are the size and shape of iPSC-derived cardiomyocytes. Adult ventricular cardiomyocytes have a typical rod-like shape and are relatively large cells with lengths of about 100 µm and diameters of 10–25 µm [471]. In contrast, iPSC-derived cardiomyocytes are much smaller [472] and are morphologically heterogeneous. The geometry of iPSC-derived cardiomyocytes ranges from round to rectangular or polygonal shapes [473,474]. In adult ventricular cardiomyocytes, the sarcomeric structure is highly organized and the Z-bands are in parallel with the intercalated disc. On the contrary, iPSC-derived cardiomyocytes have a more irregular and amorphous sarcomeric organization with diverse orientations [462,475]. In human myocardial tissue, the closed-ends of the plasma membranes connect the cardiomyocytes longitudinally and these ends of the cardiomyocytes “cylinders” are called intercalated discs. Multi-protein complexes mediate the cell–cell interactions at the intercalated discs and are subdivided into desmosomes, adherens, and gap junctions [476]. Although desmosomes and adherens junctions are also formed in iPSC-derived cardiomyocytes [472,477], the cellular distribution of these cell–cell junctions are not conserved [478,479]. Another important difference is the number of nuclei. Whereas a significant number of the human cardiomyocytes in vivo are binuclear cells [480], iPSC-derived cardiomyocytes are mononuclear cells [481]. In addition, there are significant differences in contraction and electrical properties of iPSC-derived cardiomyocytes in comparison to adult ones [474]. In summary, the structural and functional properties of iPSC-derived cardiomyocytes are more similar to fetal cardiomyocytes than to adult cardiomyocytes [482]. To overcome these limitations, different natural engineering approaches were established to drive cardiomyocytes maturation. One method is to stimulate the cardiomyocytes with electrical or mechanical impulses [483]. The composition of the extracellular matrix can also affect the interaction of the CMs, therefore influencing the cellular behavior [484,485]. Another promising approach is the co-culture of iPSC-derived cardiomyocytes with non-cardiomyocytes, enabling a more likely cardiac environment with different cellular interactions [486]. Physical, chemical, electrical, and genetic factors are being tested as stimuli for further maturation [487]. However, maturation of iPSC-derived cardiomyocytes is incompletely understood at the molecular level and more studies are needed in future.

10. Testing of Gene Therapies Using iPSC-Derived Cardiomyocytes as in Vitro Models

An interesting research topic is the development of personalized therapeutic strategies for genetic cardiomyopathies in vitro. Beyond the opportunities that reprogramming technologies offer for therapeutic myocardial regeneration, iPSC-derived cardiomyocytes are a promising platform to develop and test different gene therapies for genetic, non-ischemic cardiomyopathies. In general, the pathomechanisms of inherited cardiomyopathies can be classified into loss of function (LOF) or gain of function (GOF) mechanisms. LOF can be caused by (haplo)insufficiency or by the expression of non-functional proteins. For example, several HCM-associated MYBPC3 mutations cause haploinsufficiency [415,488]. GOF is caused by mutant and toxic proteins such as those shown for several DES missense mutations [489,490].

Genome editing using CRISPR-Cas9 or TALENs has been applied to repair different mutations in iPSC-derived cardiomyocytes. After the insertion of DSBs, iPSCs repair these DSBs using NHEJ or HDR. Template molecules like oligonucleotides, plasmids, PCR products, or even the second chromosome might be used for HDR. Recently, Ma et al. even applied CRISPR-Cas9 for the repair of a pathogenic MYBPC3 mutation in human pre-implanted embryos [491]. However, because the efficiency of HDR is low, the direct repair of mutations in iPSCs via genome editing is challenging. Therefore, single iPSC clones were frequently generated in vitro and the direct translational transfer of this method is consequently limited. A second therapeutic strategy is exon skipping [492]. Exon skipping corrects the open reading frame (ORF) of an affected gene via skipping of the mutant or multiple exons and restores the expression of the truncated, but still functional, protein. For this approach, specific antisense oligonucleotides binding to the mutant exons can be used [493]. Besides its application in iPSC-derived cardiomyocytes carrying mutations in DMD [494] or TTN [377], antisense-mediated exon skipping was also directly applied in human patients with Duchenne’s muscular dystrophy [495]. Recently, Eric Olson’s group applied CRISPR-CPF1 or -Cas9-mediated genome editing for exon skipping in iPSC-derived cardiomyocytes [379,496,497]. Prondzynski et al. applied trans-splicing and total gene replacement for the artificial increased expression of MYBPC3 in iPSC-derived cardiomyocytes carrying a heterozygous frameshift mutation in MYBPC3 [419]. The authors used adeno-associated viruses (serotype 2/9, AAV2/9) for the transduction of iPSC-derived cardiomyocytes with 5′- and 3′-pre-trans-splicing molecules and the total cDNA of MYBPC3. However, the efficiency of the trans-splicing approach was low. In contrast, the total gene replacement strategy increased the MYBPC3 expression to over 80% in comparison with wild-type controls and was able to prevent cellular hypertrophy [419].

The combination of the iPSC-derived cardiomyocytes platform with gene therapy tools is a promising therapeutic approach enabling pre-clinical demonstration of proof-of-principle for inherited cardiomyopathies.

11. Summary

Human iPSC-derived cardiomyocytes represent the only available human cellular model for the direct functional analysis of specific genetic cardiomyopathies and might therefore overcome the limitation of species differences. Impressive progress in the reprogramming and differentiation procedure during the last decade allows, in combination with novel genome editing techniques like CRISPR-Cas9, for the development of defined/patient specific cardiomyocyte models including generation of their isogenic control lines. In summary, iPSC-derived cardiomyocytes have been used for: (a) the characterization of genetic variants of unknown significance, which might be helpful for genetic counseling [375]; (b) analyses of the molecular pathomechanisms [415]; and (c) the development of specific therapies [377,497].

However, the cellular and molecular crosstalk between inflammatory cells, fibroblasts, myoblasts, and cardiomyocytes is difficult to model using iPSC-derived cardiomyocytes. Therefore, in our opinion, iPSC-derived cardiomyocytes should also be combined with animal models or with ex vivo investigations of explanted human myocardial tissue whenever possible to overcome the specific limitations of iPSC-derived cardiomyocytes.

Interestingly, for some genes like DMD, PKP2, MYBPC3, or MYH7, several different iPSC lines have been generated. In contrast, for rare cardiomyopathy genes, e.g., TMEM43, no iPSC lines have been developed yet. The genetic analysis in the past few decades has revealed a high heterogeneity of inherited, non-ischemic cardiomyopathies. In our view, it is therefore important to generate further novel iPSC lines also carrying mutations in rare cardiomyopathy genes to compare the molecular differences and commonalities leading to non-ischemic cardiomyopathies. Hopefully, iPSC-derived cardiomyocytes will contribute to unravelling the pathomechanisms of genetic cardiomyopathies and will help in efficient drug development in future.

Gene names follow the official guidelines of the HUGO Gene Nomenclature Committee (HGNC, https://www.genenames.org/) [498].

Abbreviations

ACMG American College of Medical Genetics and Genomics Institute
ACM Arrhythmogenic Cardiomyopathy
CM Cardiomyopathy
DCM Dilated Cardiomyopathy
ESC Embryonic Stem Cell
HCM Hypertrophic Cardiomyopathy
iPSC Induced Pluripotent Stem Cell
HTx Heart Transplantation
NCCM Non-Compaction Cardiomyopathy
MP Myopathy
NMD Nonsense Mediated RNA Decay
RCM Restrictive Cardiomyopathy

Author Contributions

Writing and original draft preparation—A.B., H.E., and S.R; figure preparation—A.B.; review and editing—M.A.D., A.G., J.G., and H.M.

Funding

A.B., J.G., and H.M. are thankful for financial support of the German Foundation for Heart Research (DSHF, F07/17) and by the University of Bielefeld (Forschungsfonds Medizin in der Region OWL). H.E. received a Kaltenbach scholarship from the German Heart Foundation. H.M. received a grant from the German Research Foundation (DFG, MI-1146/2-1).

Conflicts of Interest

The authors declare no conflict of interest.

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