Reply to 'Are atrial human pluripotent stem cell-derived cardiomyocytes ready to identify drugs that beat atrial fibrillation?'
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SUBMITTER: Shiti A
PROVIDER: S-EPMC7979785 | biostudies-literature | 2021 Mar
REPOSITORIES: biostudies-literature
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Reply to 'Are atrial human pluripotent stem cell-derived cardiomyocytes ready to identify drugs that beat atrial fibrillation?'
Shiti Assad A Goldfracht Idit I Shaheen Naim N Protze Stephanie S Gepstein Lior L
Nature communications 20210319 1
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Project description:Mutations in SCN5A, encoding the cardiac sodium channel, are linked with familial atrial fibrillation (AF) but the underlying pathophysiologic mechanisms and implications for therapy remain unclear. To characterize the pathogenesis of AF-linked SCN5A mutations, we generated patient-specific induced pluripotent stem cell-derived atrial cardiomyocytes (iPSC-aCMs) from two kindreds carrying SCN5A mutations (E428K and N470K) and isogenic controls using CRISPR-Cas9 gene editing. We showed that mutant AF iPSC-aCMs exhibited spontaneous arrhythmogenic activity with beat-to-beat irregularity, prolonged action potential duration, and triggered-like beats. Single-cell recording revealed enhanced late sodium currents (INa,L) in AF iPSC-aCMs that were absent in a heterologous expression model. Gene expression profiling of AF iPSC-aCMs showed differential expression of the nitric oxide (NO)-mediated signaling pathway underlying enhanced INa,L. We showed that patient-specific AF iPSC-aCMs exhibited striking in vitro electrophysiological phenotype of AF-linked SCN5A mutations, and transcriptomic analyses supported that the NO signaling pathway modulated the INa,L and triggered AF.
| S-EPMC8190590 | biostudies-literature
Project description:Atrial fibrillation (AF) is a type of sustained arrhythmia in humans often characterized by devastating alterations to the cardiac conduction system as well as the structure of the atria. AF can lead to decreased cardiac function, heart failure, and other complications. Long non-coding RNAs (lncRNAs) have been shown to play important roles in the cardiovascular system, including AF; however, a large group of lncRNAs is not conserved between mouse and human. Furthermore, AF has complex networks showing variations in mechanisms in different species, making it challenging to utilize conventional animal models to investigate the functional roles and potential therapeutic benefits of lncRNAs for AF. Fortunately, pluripotent stem cell (PSC)-derived cardiomyocytes (CMs) offer a reliable platform to study lncRNA functions in AF because of certain electrophysiological and molecular similarities with native human CMs. In this review, we first summarize the broad aspects of lncRNAs in various heart disease settings, then focus on their potential roles in AF development and pathophysiology. We also discuss current uses of PSCs in AF research and describe how these studies could be developed into novel therapeutics for AF and other cardiovascular diseases.
| S-EPMC7432754 | biostudies-literature
Project description:AimsAtrial fibrillation (AF) is associated with tachycardia-induced cellular electrophysiology alterations which promote AF chronification and treatment resistance. Development of novel antiarrhythmic therapies is hampered by the absence of scalable experimental human models that reflect AF-associated electrical remodelling. Therefore, we aimed to assess if AF-associated remodelling of cellular electrophysiology can be simulated in human atrial-like cardiomyocytes derived from induced pluripotent stem cells in the presence of retinoic acid (iPSC-aCM), and atrial-engineered human myocardium (aEHM) under short term (24 h) and chronic (7 days) tachypacing (TP).Methods and resultsFirst, 24-h electrical pacing at 3 Hz was used to investigate whether AF-associated remodelling in iPSC-aCM and aEHM would ensue. Compared to controls (24 h, 1 Hz pacing) TP-stimulated iPSC-aCM presented classical hallmarks of AF-associated remodelling: (i) decreased L-type Ca2+ current (ICa,L) and (ii) impaired activation of acetylcholine-activated inward-rectifier K+ current (IK,ACh). This resulted in action potential shortening and an absent response to the M-receptor agonist carbachol in both iPSC-aCM and aEHM subjected to TP. Accordingly, mRNA expression of the channel-subunit Kir3.4 was reduced. Selective IK,ACh blockade with tertiapin reduced basal inward-rectifier K+ current only in iPSC-aCM subjected to TP, thereby unmasking an agonist-independent constitutively active IK,ACh. To allow for long-term TP, we developed iPSC-aCM and aEHM expressing the light-gated ion-channel f-Chrimson. The same hallmarks of AF-associated remodelling were observed after optical-TP. In addition, continuous TP (7 days) led to (i) increased amplitude of inward-rectifier K+ current (IK1), (ii) hyperpolarization of the resting membrane potential, (iii) increased action potential-amplitude and upstroke velocity as well as (iv) reversibly impaired contractile function in aEHM.ConclusionsClassical hallmarks of AF-associated remodelling were mimicked through TP of iPSC-aCM and aEHM. The use of the ultrafast f-Chrimson depolarizing ion channel allowed us to model the time-dependence of AF-associated remodelling in vitro for the first time. The observation of electrical remodelling with associated reversible contractile dysfunction offers a novel platform for human-centric discovery of antiarrhythmic therapies.
| S-EPMC10730244 | biostudies-literature
Project description:Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia treatable with antiarrhythmic drugs; however, patient responses remain highly variable. Human induced pluripotent stem cell-derived atrial cardiomyocytes (iPSC-aCMs) are useful for discovering precision therapeutics, but current platforms yield phenotypically immature cells and are not easily scalable for high-throughput screening. Here, primary adult atrial, but not ventricular, fibroblasts induced greater functional iPSC-aCM maturation, partly through connexin-40 and ephrin-B1 signaling. We developed a protein patterning process within multiwell plates to engineer patterned iPSC-aCM and atrial fibroblast coculture (PC) that significantly enhanced iPSC-aCM structural, electrical, contractile, and metabolic maturation for 6+ weeks compared to conventional mono-/coculture. PC displayed greater sensitivity for detecting drug efficacy than monoculture and enabled the modeling and pharmacological or gene editing treatment of an AF-like electrophysiological phenotype due to a mutated sodium channel. Overall, PC is useful for elucidating cell signaling in the atria, drug screening, and modeling AF.
| S-EPMC10798559 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2024-01-19 | GSE239322 | GEO
Project description:Atrial fibrillation (AF)-induced peripheral microcirculatory alterations have poorly been investigated. The present study aims to expand current knowledge through a beat-to-beat analysis of non-invasive finger photoplethysmography (PPG) in AF patients restoring sinus rhythm by electrical cardioversion (ECV). Continuous non-invasive arterial blood pressure and left middle finger PPG pulse oximetry waveform (POW) signals were continuously recorded before and after elective ECV of consecutive AF or atrial flutter (AFL) patients. The main metrics (mean, standard deviation, coefficient of variation), as well as a beat-to-beat analysis of the pulse pressure (PP) and POW beat-averaged value (aPOW), were computed to compare pre- and post-ECV phases. 53 patients (mean age 69 ± 8 years, 79% males) were enrolled; cardioversion was successful in restoring SR in 51 (96%) and signal post-processing was feasible in 46 (87%) patients. In front of a non-significant difference in mean PP (pre-ECV: 51.96 ± 13.25, post-ECV: 49.58 ± 10.41 mmHg; p = 0.45), mean aPOW significantly increased after SR restoration (pre-ECV: 0.39 ± 0.09, post-ECV: 0.44 ± 0.06 a.u.; p < 0.001). Moreover, at beat-to-beat analysis linear regression yielded significantly different slope (m) for the PP (RR) relationship compared to aPOW(RR) [PP(RR): 0.43 ± 0.18; aPOW(RR): 1.06 ± 0.17; p < 0.001]. Long (> 95th percentile) and short (< 5th percentile) RR intervals were significantly more irregular in the pre-ECV phases for both PP and aPOW; however, aPOW signal suffered more fluctuations compared to PP (p < 0.001 in both phases). Present findings suggest that AF-related hemodynamic alterations are more manifest at the peripheral (aPOW) rather than at the upstream macrocirculatory level (PP). Restoring sinus rhythm increases mean peripheral microvascular perfusion and decreases variability of the microvascular hemodynamic signals. Future dedicated studies are required to determine if AF-induced peripheral microvascular alterations might relate to long-term prognostic effects.
| S-EPMC10130175 | biostudies-literature
Project description:Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia treatable with antiarrhythmic drugs, but patient responses are highly variable. Human induced pluripotent stem cell-derived atrial cardiomyocytes (iPSC-aCMs) are useful for discovering precision therapeutics, but current platforms yield an immature cellular phenotype and are not easily scalable for high-throughput screening. Here, we report that primary adult atrial, but not ventricular, fibroblasts induced greater functional iPSC-aCM maturation, partly through connexin-40 and ephrin-B1 signaling. We developed a protein patterning process within industry-standard multiwell plates to engineer patterned co-culture (PC) of iPSC-aCMs and atrial fibroblasts that significantly enhanced iPSC-aCM structural, electrical, contractile, and metabolic maturation for 6+ weeks versus conventional mono-/co-cultures. PC displayed greater sensitivity for detecting drug efficacy than monocultures, and enabled the modeling and pharmacological or gene editing treatment of an AF-like electrophysiological phenotype due to a sodium channel mutation. In conclusion, PC is useful to elucidate heterotypic cell signaling in the atria, drug screening, and to model AF.
2024-01-19 | GSE239321 | GEO
Project description:Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia treatable with antiarrhythmic drugs, but patient responses are highly variable. Human induced pluripotent stem cell-derived atrial cardiomyocytes (iPSC-aCMs) are useful for discovering precision therapeutics, but current platforms yield an immature cellular phenotype and are not easily scalable for high-throughput screening. Here, we report that primary adult atrial, but not ventricular, fibroblasts induced greater functional iPSC-aCM maturation, partly through connexin-40 and ephrin-B1 signaling. We developed a protein patterning process within industry-standard multiwell plates to engineer patterned co-culture (PC) of iPSC-aCMs and atrial fibroblasts that significantly enhanced iPSC-aCM structural, electrical, contractile, and metabolic maturation for 6+ weeks versus conventional mono-/co-cultures. PC displayed greater sensitivity for detecting drug efficacy than monocultures, and enabled the modeling and pharmacological or gene editing treatment of an AF-like electrophysiological phenotype due to a sodium channel mutation. In conclusion, PC is useful to elucidate heterotypic cell signaling in the atria, drug screening, and to model AF.
2024-01-19 | GSE239317 | GEO
Project description:Our study aims to illustrate the potential use of atrial iPSC-CMs for modeling AF in a dish, elucidating the underlying cellular mechanisms, and identifying novel mechanism-based therapies custom-tailored for individual patients
2021-06-16 | GSE154084 | GEO
Project description:The sinoatrial node is the main impulse-generating tissue in the heart. Atrioventricular conduction block and arrhythmias caused by sinoatrial node dysfunction are clinically important and generally treated with electronic pacemakers. Although an excellent solution, electronic pacemakers incorporate limitations that have stimulated research on biological pacing. To assess the suitability of potential biological pacemakers, we tested the hypothesis that the spontaneous electric activity of human embryonic stem cell-derived cardiomyocytes (hESC-CMs) and induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) exhibit beat rate variability and power-law behavior comparable to those of human sinoatrial node.We recorded extracellular electrograms from hESC-CMs and iPSC-CMs under stable conditions for up to 15 days. The beat rate time series of the spontaneous activity were examined in terms of their power spectral density and additional methods derived from nonlinear dynamics. The major findings were that the mean beat rate of hESC-CMs and iPSC-CMs was stable throughout the 15-day follow-up period and was similar in both cell types, that hESC-CMs and iPSC-CMs exhibited intrinsic beat rate variability and fractal behavior, and that isoproterenol increased and carbamylcholine decreased the beating rate in both hESC-CMs and iPSC-CMs.This is the first study demonstrating that hESC-CMs and iPSC-CMs exhibit beat rate variability and power-law behavior as in humans, thus supporting the potential capability of these cell sources to serve as biological pacemakers. Our ability to generate sinoatrial-compatible spontaneous cardiomyocytes from the patient's own hair (via keratinocyte-derived iPSCs), thus eliminating the critical need for immunosuppression, renders these myocytes an attractive cell source as biological pacemakers.
| S-EPMC3697086 | biostudies-literature