Human Induced Pluripotent Stem Cells as a Platform for Personalized and Precision Cardiovascular Medicine

Matsa, Elena; Ahrens, J; Wu, Joseph C.

doi:10.1152/physrev.00036.2015

Cited by 95 publications

(83 citation statements)

References 327 publications

(265 reference statements)

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“…This constitutes a significant advance beyond planar electrode arrays, which require hPSC-CM populations of carefully validated purity 29 , while retaining the throughput of multielectrode arrays. Finally, the nanopillar electrodes do not require signal averaging and can thus measure arrhythmic behavior in diseases such as LQTS and hypertrophic cardiomyopathy, lending the platform to patient-in-a-dish type applications 30 .…”

Section: Discussionmentioning

confidence: 99%

Accurate nanoelectrode recording of human pluripotent stem cell-derived cardiomyocytes for assaying drugs and modeling disease

et al. 2017

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The measurement of the electrophysiology of human pluripotent stem cell-derived cardiomyocytes is critical for their biomedical applications, from disease modeling to drug screening. Yet, a method that enables the high-throughput intracellular electrophysiology measurement of single cardiomyocytes in adherent culture is not available. To address this area, we have fabricated vertical nanopillar electrodes that can record intracellular action potentials from up to 60 single beating cardiomyocytes. Intracellular access is achieved by highly localized electroporation, which allows for low impedance electrical access to the intracellular voltage. Herein, we demonstrate that this method provides the accurate measurement of the shape and duration of intracellular action potentials, validated by patch clamp, and can facilitate cellular drug screening and disease modeling using human pluripotent stem cells. This study validates the use of nanopillar electrodes for myriad further applications of human pluripotent stem cell-derived cardiomyocytes such as cardiomyocyte maturation monitoring and electrophysiology-contractile force correlation. There have been many efforts to generate cardiomyocytes (CMs) derived from human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs) due to the difficulty in obtaining human cardiac tissue by other methods 7 . In the last decade, efficient and reliable protocols, such as the embryoid body method and the monolayer differentiation method have been established to generate hPSC-CMs within 2 weeks and with 470% efficiency 8,9 . Critically, hPSC-CMs exhibit key cardiomyocyte properties, expressing the expected ion channels, exhibiting human cardiac-type action potentials, and containing functional sarcomeres.Despite their potential, applications of hPSC-CMs have been hampered by the cells' intrinsic heterogeneity and the quality of functional assays for monitoring their electrophysiology. First, hPSC-CMs are intrinsically heterogeneous, consisting of three subpopulations: atrial-, ventricular-, and nodal-like 10 . Furthermore, electrophysiology measurements have shown that the shapes of action potentials vary significantly between studies and within studies among different cell lines and differentiation methods 11,12 . Therefore, the high heterogeneity among hPSC-CMs requires that a large number of cells be analyzed to generate statistically meaningful conclusions.The gold standard for measuring cardiomyocyte electrophysiology is manual patch clamp; however, this technique is laborious

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Section: Discussionmentioning

confidence: 99%

Accurate nanoelectrode recording of human pluripotent stem cell-derived cardiomyocytes for assaying drugs and modeling disease

et al. 2017

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“…For example, the application of human induced pluripotent stem cells (iPSCs), which could store personalized big data, could be an important component in personalized medicine—a patient's personalized database 50, 51. With the tremendous advances in “next‐generation” diagnostic techniques, thousands of mutations have been found and the origin of many diseases understood in greater depth 128.…”

Section: Outlook For Personalized and Precision Medicinementioning

confidence: 99%

“…A variety of modified EVs, including EVs specifically enriched in mRNA,42 miRNA,12, 43 and small interfering RNA (siRNA),20, 44 EVs with membrane modification,45, 46 and EVs carrying small molecule drugs47 and superparamagnetic iron oxide nanoparticles48 have been developed. As the era of personalized and precision medicine continues to develop, the demands of both the targeting ability toward pathological organization combined with limited damage to normal tissues49 to minimize side effects (precision medicine) and freely assembled agents based on a patient's personalized database50, 51 to maximize therapeutic effects (personalized medicine) will continually increase.…”

Section: Introductionmentioning

confidence: 99%

Modularized Extracellular Vesicles: The Dawn of Prospective Personalized and Precision Medicine

2018

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Extracellular vesicles (EVs) are ubiquitous nanosized membrane vesicles consisting of a lipid bilayer enclosing proteins and nucleic acids, which are active in intercellular communications. EVs are increasingly seen as a vital component of many biological functions that were once considered to require the direct participation of stem cells. Consequently, transplantation of EVs is gradually becoming considered an alternative to stem cell transplantation due to their significant advantages, including their relatively low probability of neoplastic transformation and abnormal differentiation. However, as research has progressed, it is realized that EVs derived from native‐source cells may have various shortcomings, which can be corrected by modification and optimization. To date, attempts are made to modify or improve almost all the components of EVs, including the lipid bilayer, proteins, and nucleic acids, launching a new era of modularized EV therapy through the “modular design” of EV components. One high‐yield technique, generating EV mimetic nanovesicles, will help to make industrial production of modularized EVs a reality. These modularized EVs have highly customized “modular design” components related to biological function and targeted delivery and are proposed as a promising approach to achieve personalized and precision medicine.

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“…7,8 In the cardiac field, hiPSCs were established from healthy individuals and from patients inflicted with acquired 9 and several types of inherited cardiac disorders. 10,11 Patient-specific hiPSC-derived cardiomyocyte (hiPSC-CM) models of different inherited arrhythmogenic syndromes (including the long-QT, [12][13][14][15] Brugada, 16 and sodium channel overlap 17 syndromes; arrhythmogenic right ventricular cardiomyopathy 18,19 ; and both types of CPVT [20][21][22][23][24][25][26][27][28][29] ) were…”

Section: See Editorial By LI Et Almentioning

confidence: 99%

Patient-Specific Drug Screening Using a Human Induced Pluripotent Stem Cell Model of Catecholaminergic Polymorphic Ventricular Tachycardia Type 2

Maizels

Huber

Arbel

et al. 2017

Circ: Arrhythmia and Electrophysiology

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Background-Catecholaminergic polymorphic ventricular tachycardia type 2 (CPVT2) results from autosomal recessive CASQ2 mutations, causing abnormal Ca 2+ -handling and malignant ventricular arrhythmias. We aimed to establish a patient-specific human induced pluripotent stem cell (hiPSC) model of CPVT2 and to use the generated hiPSC-derived cardiomyocytes to gain insights into patient-specific disease mechanism and pharmacotherapy. Methods and Results-hiPSC cardiomyocytes were derived from a CPVT2 patient (D307H-CASQ2 mutation) and from healthy controls. Laser-confocal Ca 2+ and voltage imaging showed significant Ca 2+ -transient irregularities, marked arrhythmogenicity manifested by early afterdepolarizations and triggered arrhythmias, and reduced threshold for store overload-induced Ca 2+ -release events in the CPVT2-hiPSC cardiomyocytes when compared with healthy control cells. Pharmacological studies revealed the prevention of adrenergic-induced arrhythmias by β-blockers (propranolol and carvedilol), flecainide, and the neuronal sodium-channel blocker riluzole; a direct antiarrhythmic action of carvedilol (independent of its α/β-adrenergic blocking activity), flecainide, and riluzole; and suppression of abnormal Ca 2+ cycling by the ryanodine stabilizer JTV-519 and carvedilol. Mechanistic insights were gained on the different antiarrhythmic actions of the aforementioned drugs, with carvedilol and JTV-519 (but not flecainide or riluzole) acting primarily through sarcoplasmic reticulum stabilization. Finally, comparable outcomes were found between flecainide and labetalol antiarrhythmic effects in vitro and the clinical results in the same patient.Conclusions-These results demonstrate the ability of hiPSCs cardiomyocytes to recapitulate CPVT2 disease phenotype and drug response in the culture dish, to provide novel insights into disease and drug therapy mechanisms, and potentially to tailor patient-specific drug therapy. (Circ Arrhythm Electrophysiol. 2017;10:e004725.

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Human Induced Pluripotent Stem Cells as a Platform for Personalized and Precision Cardiovascular Medicine

Cited by 95 publications

References 327 publications

Accurate nanoelectrode recording of human pluripotent stem cell-derived cardiomyocytes for assaying drugs and modeling disease

Accurate nanoelectrode recording of human pluripotent stem cell-derived cardiomyocytes for assaying drugs and modeling disease

Modularized Extracellular Vesicles: The Dawn of Prospective Personalized and Precision Medicine

Patient-Specific Drug Screening Using a Human Induced Pluripotent Stem Cell Model of Catecholaminergic Polymorphic Ventricular Tachycardia Type 2

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