Cardiomyopathy phenotypes in human-induced pluripotent stem cell-derived cardiomyocytes—a systematic review

Abstract

Human-induced pluripotent stem cells (hiPSC) can be differentiated to cardiomyocytes at high efficiency and are increasingly used to study cardiac disease in a human context. This review evaluated 38 studies on hypertrophic (HCM) and dilated cardiomyopathy (DCM) of different genetic causes asking to which extent published data allow the definition of an in vitro HCM/DCM hiPSC-CM phenotype. The data are put in context with the prevailing hypotheses on HCM/DCM dysfunction and pathophysiology. Relatively consistent findings in HCM not reported in DCM were larger cell size (156 ± 85%, n = 15), more nuclear localization of nuclear factor of activated T cells (NFAT; 175 ± 65%, n = 3), and higher β-myosin heavy chain gene expression levels (500 ± 547%, n = 8) than respective controls. Conversely, DCM lines showed consistently less force development than controls (47 ± 23%, n = 9), while HCM forces scattered without clear trend. Both HCM and DCM lines often showed sarcomere disorganization, higher NPPA/NPPB expression levels, and arrhythmic beating behaviour. The data have to be taken with the caveat that reporting frequencies of the various parameters (e.g. cell size, NFAT expression) differ widely between HCM and DCM lines, in which data scatter is large and that only 9/38 studies used isogenic controls. Taken together, the current data provide interesting suggestions for disease-specific phenotypes in HCM/DCM hiPSC-CM but indicate that the field is still in its early days. Systematic, quantitative comparisons and robust, high content assays are warranted to advance the field.

3D Co-culture of hiPSC-Derived Cardiomyocytes With Cardiac Fibroblasts Improves Tissue-Like Features of Cardiac Spheroids

“…Since CF produce native extracellular matrix (ECM) proteins and show bidirectional signaling crosstalk with cardiomyocytes, they play key roles in the development, maintenance, and remodeling of the ventricular myocardium (Miragoli et al, 2006;Souders et al, 2009;Bowers et al, 2010;Ongstad and Kohl, 2016). The use of human heart cells improves the relevance of the model system, due to identical human genetic background with a complete organotypic, however immature, protein expression pattern (Eschenhagen and Carrier, 2019). Furthermore, human cell-derived models offer the possibility of drug testing in a framework of personalized medicine (van Meer Abbreviations: 2D, two-dimensional; 3D, three-dimensional; alpha-SMA, alpha smooth muscle actin (alpha actin 2); CF, cardiac fibroblasts; DAPI, 4 ′ ,6-diamidin-2-phenylindol; DMEM, Dulbecco's modified eagle medium; Doxo, doxorubicin hydrochloride (adriamycin); ECM, extracellular matrix; FPS, frames per second; HCF, human cardiac fibroblasts; hiPSC-CMs, human induced-pluripotent stem cell-derived cardiomyocytes; OCT, optimal cutting temperature compound; qPCR, quantitative polymerase chain reaction; SDS, sodium dodecyl sulfate; SEM, scanning electron microscopy; TEM, transmission electron microscopy.…”

Inherited cardiac diseases, pluripotent stem cells, and genome editing combined—the past, present, and future

“…50,51 Some studies have also observed features such as increased MYH7 gene expression and nuclear accumulation of the transcription factor NFAT, 50,52 although whether these are disease specific remain contentious. 13 Finally, dysfunctional Ca 2+ dynamics appears to be a key pathological mechanism observed in hiPSC-CM models of HCM, although this is not consistently reflected in changes to contractile force or kinetics. 53,54 Finally, although ACM was initially believed to be a disease affecting just the right ventricle and was characterized by ventricular arrhythmias and fibrofatty tissue deposits in the myocardium, 55 the identification of its genetic basis as well as the phenotyping of large patient cohorts determined that both ventricles could be affected.…”

“…The list of disease models used in the analysis is provided in Supplemental Table S1. This list was generated by initially examining referenced articles from multiple comprehensive reviews published in the field, with more recent articles identified by performing a PubMed literature search using the query: [(“pluripotent stem cell”[Title/Abstract] AND ((arrhythmia[Title/Abstract] OR channelopathy[Title/Abstract]) OR cardiomyopathy[Title/Abstract])) AND (“2018”[PDAT]: “3000”[PDAT])]. The resulting publication list was then screened for additional relevant publications that were then examined manually.…”

“…The list of disease models used in the analysis is provided in Supplemental Table S1. This list was generated by initially examining referenced articles from multiple comprehensive reviews published in the field, [9][10][11][12][13][14] . The resulting publication list was then screened for additional relevant publications that were then examined manually.…”

Modeling Hypertrophic Cardiomyopathy: Mechanistic Insights and Pharmacological Intervention

“…In the past 6 years, hPSC-CMs have been extensively used for modeling HCM [15,16]. Lan et al pioneered the field by reporting in vitro phenotypes of R663H-β-MHC cardiomyocytes, namely increased multinucleation (48.3%) relative to healthy controls (22.1%), with stark abnormalities in calcium handling (about threefold higher percentage of cells displaying arrhythmias) [60].…”