Mitochondrial Dysfunctions Contribute to Hypertrophic Cardiomyopathy in Patient iPSC-Derived Cardiomyocytes with MT-RNR2 Mutation

Li, Shishi; Pan, Huaye; Tan, Chung-I; Sun, Ya‐Ping; Song, Yumeng; Zhang, Xuan; Yang, Wei; Wang, Xuexiang; Li, Dan; Dai, Yu; Ma, Qiang; Xu, Chenming; Zhu, Xuemei; Kang, Lijun; Fu, Yong; Xu, Xuejun; Shu, Jing; Zhou, Naiming; Feng, Huan; Qin, Dajiang; Huang, Wendong; Liu, Zhong; Yan, Qingfeng

doi:10.1016/j.stemcr.2018.01.013

Cited by 71 publications

(57 citation statements)

References 63 publications

(78 reference statements)

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“…The capacitance data are consistent across different studies (e.g. 60 pF in hiPSC-CM [ 93 ], 27 pF in hiPSC-CM [ 52 , 54 ], ~ 60 pF in human atrial cardiomyocytes [ 97 ]). Possibly, the ratio between membrane capacitance and cell volume, which varies between species and the developmental stage (pF/pl = 4–9 [ 83 ]), is unusually high in hiPSC-CM.…”

Section: Hcm and Dcm Phenotypes In Hipsc-cardiomyocytessupporting

confidence: 77%

“…down, GB3 accumulation, low beating rate, arrhythmias No [ 15 ] LAMP2 Het c.129– 130insAT) Het c.64+1G>A Danon n.d. n.d. n.d. n.d. n.d. Mitochondrial abnormalities, decreased autophagic flux No Yes [ 34 ] MYBPC3 Het c.1358_1359insC HCM n.d. n.d. n.d. + 65% n.d. cMyBPC haploinsufficiency, BNP, MYH7 and others up Corrected by gene therapy No [ 76 ] PRKAG2 Het Arg302Gln HCM + WPW n.d. n.d. n.d. + 10–30% n.d. MDP, APD +/−, If +/−, AP irregularity, RR scatter + 500% Yes Yes [ 5 ] SCO2 Hom c.577G>A CpHet c.418G>A/c.17Ins19 HCM syndrome +/− (??) n.d. n.d. n.d. n.d. Mitochondrial abnormalities, no Iso or Ca 2+ response, DAD, arrhythmic response to Iso No Yes [ 31 ] MT-RNR2 m.2336T>C Mitochondrial HCM n.d. n.d. n.d. + 30% n.d. NPPA , NPPB , NFAT up, slightly increased intracellular calcium, SR store, reduced I Ca , APD prolonged, arrhythmias, RMP − 55, upstroke 5–10 v/s, DAD No Yes [ 52 ] MYL3 Het c.170C-A, Exac 0.0001154, introduced 170C-g and MYBPC3 Het p.Val321Met HCM-associated VUS n.d. n.d. n.d. +/− (also in mut) n.d. No phenotype detected in VU...…”

Section: Hcm and Dcm Phenotypes In Hipsc-cardiomyocytesmentioning

confidence: 99%

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

Eschenhagen

Carrier

2018

Pflugers Arch - Eur J Physiol

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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.

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Section: Hcm and Dcm Phenotypes In Hipsc-cardiomyocytessupporting

confidence: 77%

Section: Hcm and Dcm Phenotypes In Hipsc-cardiomyocytesmentioning

confidence: 99%

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

Eschenhagen

Carrier

2018

Pflugers Arch - Eur J Physiol

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“…It is implicated that mitochondrial dysfunction crucially contributes to electrophysiological abnormalities in hiPSC-CMs. 46 Presumably, the decrease of beat rate and spike amplitude in hiPSC-CMs observed in the present study might be also attributed to mitochondrial dysfunction. Clinically, more attention should be paid to detect the deleterious cardiac effects in the patients related to ZnO NPs exposure such as electrocardiogram and serum enzymes.…”

Section: Discussionmentioning

confidence: 56%

<p>Zinc Oxide Nanoparticles Induce Mitochondrial Biogenesis Impairment and Cardiac Dysfunction in Human iPSC-Derived Cardiomyocytes</p>

Li¹,

Li²,

Zhang³

et al. 2020

IJN

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Background: Zinc oxide nanoparticles (ZnO NPs) are one of the most widely used nanomaterials in a variety of fields such as industrial, pharmaceutical, and household applications. Increasing evidence suggests that ZnO NPs could elicit unignorable harmful effect to the cardiovascular system, but the potential deleterious effects to human cardiomyocytes remain to be elucidated. Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have been increasingly used as a promising in vitro model of cardiomyocyte in various fields such as drug cardiac safety evaluation. Herein, the present study was designed to elucidate the cardiac adverse effects of ZnO NPs and explore the possible underlying mechanism using hiPSC-CMs. Methods: ZnO NPs were characterized by transmission electron microscopy and dynamic light scattering. The cytotoxicity induced by ZnO NPs in hiPSC-CMs was evaluated by determination of cell viability and lactate dehydrogenase release. Cellular reactive oxygen species (ROS) and mitochondrial membrane potential were measured by high-content analysis (HCA). Mitochondrial biogenesis was assayed by detection of mtDNA copy number and PGC-1α pathway. Moreover, microelectrode array techniques were used to investigate cardiac electrophysiological alterations. Results: We demonstrated that ZnO NPs concentration-and time-dependently elicited cytotoxicity in hiPSC-CMs. The results from HCA revealed that ZnO NPs exposure at lowcytotoxic concentrations significantly promoted ROS generation and induced mitochondrial dysfunction. We further demonstrated that ZnO NPs could impair mitochondrial biogenesis and inhibit PGC-1α pathway. In addition, ZnO NPs at insignificantly cytotoxic concentrations were found to trigger cardiac electrophysiological alterations as evidenced by decreases of beat rate and spike amplitude. Conclusion: Our findings unveiled the potential harmful effects of ZnO NPs to human cardiomyocytes that involve mitochondrial biogenesis and the PGC-1α pathway that could affect cardiac electrophysiological function.

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“…HCM patients exhibited defects in mitochondrial functions and ultrastructure and abnormal energy metabolism [74]. These structural and functional phenotypes were recapitulated in hiPSC-CMs carrying m.2336 T > C mutation in mitochondrial genome causing HCM [86]. They reported that HCM hiPSC-CMs expressed reduced levels of mitochondrial proteins, ATP/ADP ratio, and mitochondrial membrane potential [86].…”

Section: Hypertrophic Cardiomyopathy (Hcm)mentioning

confidence: 99%

Modelling of Genetic Cardiac Diseases

Prajapati¹,

Aalto‐Setälä²

2019

Visions of Cardiomyocyte - Fundamental Concepts of Heart Life and Disease [Working Title]

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Cardiac disease modeling is crucial to improve our understanding of the mechanism of various cardiac diseases and to discover new therapeutic approaches. Several modeling methods such as animal and computer simulations have been used to elucidate the cardiac diseases' mechanism and drug responses. However, each modeling technique has its own particular advantages and limitations. Human-based models would be particularly useful to investigate human cardiac diseases because humans and animals have differing cardiac physiologies and drug tolerability. In addition, the phenotype of cardiac diseases and response to therapeutic intervention differ not only between mutations but also among patients. Therefore, such diseases strongly demand the individualized/personalized strategies. Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) offer the striking feature of retaining the same genetic information as donor, which guide us to investigate diseases and predict response to drug treatment individually. This feature of hiPSC-CMs is superior to the conventional in vitro modeling of cardiac diseases. Thus far, hiPSC-CMs have been successfully recapitulated many monogenic and also complex genetic cardiac diseases. hiPSC-CMs could be differentiated into different types of cardiomyocytes and non-cardiomyocyte cells, which empower us to understand cardiac chamber-specific arrhythmias such as atrial fibrillation and ventricular tachycardia.

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Mitochondrial Dysfunctions Contribute to Hypertrophic Cardiomyopathy in Patient iPSC-Derived Cardiomyocytes with MT-RNR2 Mutation

Cited by 71 publications

References 63 publications

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

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

<p>Zinc Oxide Nanoparticles Induce Mitochondrial Biogenesis Impairment and Cardiac Dysfunction in Human iPSC-Derived Cardiomyocytes</p>

Modelling of Genetic Cardiac Diseases

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