Maturation status of sarcomere structure and function in human iPSC-derived cardiac myocytes

Bedada, Fikru B.; Wheelwright, Matthew; Metzger, Joseph M.

doi:10.1016/j.bbamcr.2015.11.005

Cited by 118 publications

(120 citation statements)

References 96 publications

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“…; Bedada et al . ) and lack the characteristic rod‐shape morphology and uniaxially aligned sarcomeres of adult cardiomyocyte when cultured on a regular culture dish (Bedada et al . ).…”

Section: Introductionmentioning

confidence: 99%

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In vitro model to study the effects of matrix stiffening on Ca²⁺ handling and myofilament function in isolated adult rat cardiomyocytes

Deel¹,

Najafi²,

Fontoura

et al. 2017

The Journal of Physiology

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Key points This paper describes a novel model that allows exploration of matrix‐induced cardiomyocyte adaptations independent of the passive effect of matrix rigidity on cardiomyocyte function.Detachment of adult cardiomyocytes from the matrix enables the study of matrix effects on cell shortening, Ca2+ handling and myofilament function.Cell shortening and Ca2+ handling are altered in cardiomyocytes cultured for 24 h on a stiff matrix.Matrix stiffness‐impaired cardiomyocyte contractility is reversed upon normalization of extracellular stiffness.Matrix stiffness‐induced reduction in unloaded shortening is more pronounced in cardiomyocytes isolated from obese ZSF1 rats with heart failure with preserved ejection fraction compared to lean ZSF1 rats. AbstractExtracellular matrix (ECM) stiffening is a key element of cardiac disease. Increased rigidity of the ECM passively inhibits cardiac contraction, but if and how matrix stiffening also actively alters cardiomyocyte contractility is incompletely understood. In vitro models designed to study cardiomyocyte–matrix interaction lack the possibility to separate passive inhibition by a stiff matrix from active matrix‐induced alterations of cardiomyocyte properties. Here we introduce a novel experimental model that allows exploration of cardiomyocyte functional alterations in response to matrix stiffening. Adult rat cardiomyocytes were cultured for 24 h on matrices of tuneable stiffness representing the healthy and the diseased heart and detached from their matrix before functional measurements. We demonstrate that matrix stiffening, independent of passive inhibition, reduces cell shortening and Ca2+ handling but does not alter myofilament‐generated force. Additionally, detachment of adult cultured cardiomyocytes allowed the transfer of cells from one matrix to another. This revealed that stiffness‐induced cardiomyocyte changes are reversed when matrix stiffness is normalized. These matrix stiffness‐induced changes in cardiomyocyte function could not be explained by adaptation in the microtubules. Additionally, cardiomyocytes isolated from stiff hearts of the obese ZSF1 rat model of heart failure with preserved ejection fraction show more pronounced reduction in unloaded shortening in response to matrix stiffening. Taken together, we introduce a method that allows evaluation of the influence of ECM properties on cardiomyocyte function separate from the passive inhibitory component of a stiff matrix. As such, it adds an important and physiologically relevant tool to investigate the functional consequences of cardiomyocyte–matrix interactions.

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“…; Bedada et al . ) and lack the characteristic rod‐shape morphology and uniaxially aligned sarcomeres of adult cardiomyocyte when cultured on a regular culture dish (Bedada et al . ).…”

Section: Introductionmentioning

confidence: 99%

“…) and lack the characteristic rod‐shape morphology and uniaxially aligned sarcomeres of adult cardiomyocyte when cultured on a regular culture dish (Bedada et al . ). However, great progress has been made in developing methods in maturing these cells to closely mimic the adult cardiomyocyte (Yang et al .…”

Section: Introductionmentioning

confidence: 99%

In vitro model to study the effects of matrix stiffening on Ca²⁺ handling and myofilament function in isolated adult rat cardiomyocytes

Deel¹,

Najafi²,

Fontoura

et al. 2017

The Journal of Physiology

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“…In general, iPSC-CMs are considered to possess an immature phenotype that more closely resembles fetal than adult heart cells. 3,4 This is seen both structurally, in the fact that iPSC-CMs lack transverse tubules and a regular organization of sarcomeres, 27 and functionally, in features such as the contribution of sarcoplasmic reticulum Ca 2+ release 3 and the densities of particular K + channels. 28 Because of these physiological differences, drug responses observed in iPSC-CMs and adult myocytes are also expected to diverge.…”

Section: Discussionmentioning

confidence: 99%

Population-Based Mechanistic Modeling Allows for Quantitative Predictions of Drug Responses across Cell Types

Gong

Sobie

2018

Biophysical Journal

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Quantitative mismatches between human physiology and experimental models can be problematic for the development of effective therapeutics. When the effects of drugs on human adult cardiac electrophysiology are of interest, phenotypic differences with animal cells, and more recently stem cell-derived models, can present serious limitations. We addressed this issue through a combination of mechanistic mathematical modeling and statistical analyses. Physiological metrics were simulated in heterogeneous populations of models describing cardiac myocytes from adult ventricles and those derived from induced pluripotent stem cells (iPSC-CMs). These simulated measures were used to construct a cross-cell type regression model that predicts adult myocyte drug responses from iPSC-CM behaviors. We found that (1) quantitatively accurate predictions of responses to selective or non-selective ion channel blocking drugs could be generated based on iPSC-CM responses under multiple experimental conditions; (2) altering extracellular ion concentrations is an effective experimental perturbation for improving the model's predictive strength; (3) the method can be extended to predict and contrast drug responses in diseased as well as healthy cells, indicating a broader application of the concept. This cross-cell type model can be of great value in drug development, and the approach, which can be applied to other fields, represents an important strategy for overcoming experimental model limitations.

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“…For one, it became evident that many protocols that were developed for the differentiation of hPSCs into functional tissue resulted in embryonic rather than adult human cell types (Bedada et al, 2015; Forster et al, 2014; Hrvatin et al, 2014; Spence et al, 2011; Takebe et al, 2013). This observation might not pose a problem for studies that aim to recapitulate cell-autonomous defects of developmental diseases that likely will become apparent after a few weeks of in vitro differentiation.…”

Section: The Power and Limitations Of Ipscsmentioning

confidence: 99%

Induced Pluripotent Stem Cells Meet Genome Editing

2016

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It is extremely rare for a single experiment to be so impactful and timely that it shapes and forecasts the experiments of the next decade. Here, we review how two such experiments --the generation of human induced pluripotent stem cells (iPSCs) and the development of CRISPR/Cas9 technology-- have fundamentally reshaped our approach to biomedical research, stem cell biology and human genetics. We will also highlight the previous knowledge that iPSC and CRISPR/Cas9 technologies were built on as this groundwork demonstrated the need for solutions and the benefits that these technologies provided, and have set the stage for their success.

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Maturation status of sarcomere structure and function in human iPSC-derived cardiac myocytes

Cited by 118 publications

References 96 publications

In vitro model to study the effects of matrix stiffening on Ca²⁺ handling and myofilament function in isolated adult rat cardiomyocytes

In vitro model to study the effects of matrix stiffening on Ca²⁺ handling and myofilament function in isolated adult rat cardiomyocytes

Population-Based Mechanistic Modeling Allows for Quantitative Predictions of Drug Responses across Cell Types

Induced Pluripotent Stem Cells Meet Genome Editing

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Maturation status of sarcomere structure and function in human iPSC-derived cardiac myocytes

Cited by 118 publications

References 96 publications

In vitro model to study the effects of matrix stiffening on Ca2+ handling and myofilament function in isolated adult rat cardiomyocytes

In vitro model to study the effects of matrix stiffening on Ca2+ handling and myofilament function in isolated adult rat cardiomyocytes

Population-Based Mechanistic Modeling Allows for Quantitative Predictions of Drug Responses across Cell Types

Induced Pluripotent Stem Cells Meet Genome Editing

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Product

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In vitro model to study the effects of matrix stiffening on Ca²⁺ handling and myofilament function in isolated adult rat cardiomyocytes

In vitro model to study the effects of matrix stiffening on Ca²⁺ handling and myofilament function in isolated adult rat cardiomyocytes