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Titin truncating variantsin hiPSC-cardiomyocytes inducepathogenic proteinopathy, sarcomeredefect and contractile dysfunction independent of the core contractilemachinery

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE183218 | GEO | 2023/01/25

REPOSITORIES: GEO

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Titin truncating variantsin hiPSC-cardiomyocytes inducepathogenic proteinopathy, sarcomeredefect and contractile dysfunction independent of the core contractilemachinery [scRNA-seq]

Project description:Titintruncating variants(TTNtv) have been identified as the single largestgenetic cause of dilated cardiomyopathy(DCM). In this studywe modeled the disease phenotypes of TTNtv-induced DCM in hiPSC-CMsusing CRISPR/Cas9 genome editing and tissue engineering technologies. Transcriptomic, cellular and micro-tissue studies revealed that TTNtv hiPSC-CMs displayed pathogenic proteinopathy, sarcomere defects, aberrant Na+channel activities and, most importantly, contractile dysfunction. These phenotypes establish a dual mechanism of poison peptide effect and haploinsufficiency that collectively contribute to DCM pathogenesis. On the other hand, TTNtv cellular defects did not interfere with normal function of the core contractile machinery, actin-myosin-troponin-Ca2+complex, and preserved the therapeutic mechanism of sarcomere modulators. Treatment of TTNtv cardiac micro-tissues with investigational sarcomere modulators augmented contractility and resulted in sustained transcriptomicchanges that promotereversalof DCM disease signatures, as revealed by single-cell RNA-seqanalysis.Taken together, our findings depict the underlying pathogenic mechanisms of TTNtv-induced DCMand demonstrate the validity of sarcomere modulators as potentialtherapeutic agentsfor this disease.

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Titin truncating variantsin hiPSC-cardiomyocytes inducepathogenic proteinopathy, sarcomeredefect and contractile dysfunction independent of the core contractilemachinery [bulk RNA-seq]

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Titin-truncating variants in hiPSC cardiomyocytes induce pathogenic proteinopathy and sarcomere defects with preserved core contractile machinery.

Project description:Titin-truncating variants (TTNtv) are the single largest genetic cause of dilated cardiomyopathy (DCM). In this study we modeled disease phenotypes of A-band TTNtv-induced DCM in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) using genome editing and tissue engineering technologies. Transcriptomic, cellular, and micro-tissue studies revealed that A-band TTNtv hiPSC-CMs exhibit pathogenic proteinopathy, sarcomere defects, aberrant Na+ channel activities, and contractile dysfunction. These phenotypes establish a dual mechanism of poison peptide effect and haploinsufficiency that collectively contribute to DCM pathogenesis. However, TTNtv cellular defects did not interfere with the function of the core contractile machinery, the actin-myosin-troponin-Ca2+ complex, and preserved the therapeutic mechanism of sarcomere modulators. Treatment of TTNtv cardiac micro-tissues with investigational sarcomere modulators augmented contractility and resulted in sustained transcriptomic changes that promote reversal of DCM disease signatures. Together, our findings elucidate the underlying pathogenic mechanisms of A-band TTNtv-induced DCM and demonstrate the validity of sarcomere modulators as potential therapeutics.

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Titin truncating variantsin hiPSC-cardiomyocytes inducepathogenic proteinopathy, sarcomeredefect and contractile dysfunction independent of the core contractilemachinery

Project description:Titin truncating variantsin hiPSC-cardiomyocytes inducepathogenic proteinopathy, sarcomeredefect and contractile dysfunction independent of the core contractilemachinery

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Titin truncating variantsin hiPSC-cardiomyocytes inducepathogenic proteinopathy, sarcomeredefect and contractile dysfunction independent of the core contractilemachinery [scRNA-seq]

Project description:Titin truncating variantsin hiPSC-cardiomyocytes inducepathogenic proteinopathy, sarcomeredefect and contractile dysfunction independent of the core contractilemachinery [scRNA-seq]

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Titin truncating variantsin hiPSC-cardiomyocytes inducepathogenic proteinopathy, sarcomeredefect and contractile dysfunction independent of the core contractilemachinery [bulk RNA-seq]

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Differentiation and Contractile Analysis of GFP-Sarcomere Reporter hiPSC-Cardiomyocytes.

Project description:Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) represent a powerful cellular platform for illuminating mechanisms of human cardiovascular disease and for pharmacological screening. Recent advances in CRISPR/Cas9-mediated genome editing technology underlie this profound utility. We have generated hiPSC-CMs harboring fluorescently-tagged sarcomeric proteins, which provide a tool to non-invasively study human sarcomere function and dysfunction. In this unit, we illustrate methods for conducting high-efficiency, small molecule-mediated differentiation of hiPSCs into cardiomyocytes, and for performing non-invasive contractile analysis through direct sarcomere tracking of GFP-sarcomere reporter hiPSC-CMs. We believe that this type of analysis can overcome sensitivity problems found in other forms of contractile assays involving hiPSC-CMs by directly measuring contractility at the fundamental contractile unit of the hiPSC-CM, the sarcomere. © 2018 by John Wiley & Sons, Inc.

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Simultaneous measurement of excitation-contraction coupling parameters identifies mechanisms underlying contractile responses of hiPSC-derived cardiomyocytes.

Project description:Cardiomyocytes from human induced pluripotent stem cells (hiPSC-CMs) are increasingly recognized as valuable for determining the effects of drugs on ion channels but they do not always accurately predict contractile responses of the human heart. This is in part attributable to their immaturity but the sensitivity of measurement tools may also be limiting. Measuring action potential, calcium flux or contraction individually misses critical information that is captured when interrogating the complete excitation-contraction coupling cascade simultaneously. Here, we develop an hypothesis-based statistical algorithm that identifies mechanisms of action. We design and build a high-speed optical system to measure action potential, cytosolic calcium and contraction simultaneously using fluorescent sensors. These measurements are automatically processed, quantified and then assessed by the algorithm. Multiplexing these three critical physical features of hiPSC-CMs allows identification of all major drug classes affecting contractility with detection sensitivities higher than individual measurement of action potential, cytosolic calcium or contraction.

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