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"Gaspard, Helen"
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Doctor Dan the Bandage Man
After watching his mother clean and bandage his scratch, Dan knows just what to do when his sister, her doll, their dog, and even his father have wounds that need tending, and earns himself a new nickname.
Book
Tracking single hiPSC-derived cardiomyocyte contractile function using CONTRAX an efficient pipeline for traction force measurement
Cardiomyocytes derived from human induced pluripotent stem cells (hiPSC-CMs) are powerful in vitro models to study the mechanisms underlying cardiomyopathies and cardiotoxicity. Quantification of the contractile function in single hiPSC-CMs at high-throughput and over time is essential to disentangle how cellular mechanisms affect heart function. Here, we present CONTRAX, an open-access, versatile, and streamlined pipeline for quantitative tracking of the contractile dynamics of single hiPSC-CMs over time. Three software modules enable: parameter-based identification of single hiPSC-CMs; automated video acquisition of >200 cells/hour; and contractility measurements via traction force microscopy. We analyze >4,500 hiPSC-CMs over time in the same cells under orthogonal conditions of culture media and substrate stiffnesses; +/− drug treatment; +/− cardiac mutations. Using undirected clustering, we reveal converging maturation patterns, quantifiable drug response to Mavacamten and significant deficiencies in hiPSC-CMs with disease mutations. CONTRAX empowers researchers with a potent quantitative approach to develop cardiac therapies.
Cardiomyocytes derived from human induced pluripotent stem cells (hiPSC-CMs) are powerful in vitro models. Here the authors report CONTRAX, an open-access, versatile, and streamlined pipeline for quantitative tracking of the contractile dynamics of single hiPSC-CMs over time at increased throughput.
Journal Article
Tamoxifen treatment ameliorates contractile dysfunction of Duchenne muscular dystrophy stem cell-derived cardiomyocytes on bioengineered substrates
Duchenne muscular dystrophy (DMD) is a progressive genetic myopathy that leads to heart failure from dilated cardiomyopathy by early adulthood. Recent evidence suggests that tamoxifen, a selective estrogen receptor modulator widely used to treat breast cancer, ameliorates DMD cardiomyopathy. However, the mechanism of action of 4-hydroxytamoxifen, the active metabolite of tamoxifen, on cardiomyocyte function remains unclear. To examine the effects of chronic 4-hydroxytamoxifen treatment, we used state-of-the-art human-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) and a bioengineered platform to model DMD. We assessed the beating rate and beating velocity of iPSC-CMs in monolayers and as single cells on micropatterns that promote a physiological cardiomyocyte morphology. We found that 4-hydroxytamoxifen treatment of DMD iPSC-CMs decreased beating rate, increased beating velocity, and ameliorated calcium-handling deficits, leading to prolonged viability. Our study highlights the utility of a bioengineered iPSC-CM platform for drug testing and underscores the potential of repurposing tamoxifen as a therapy for DMD cardiomyopathy.
Journal Article
Telomere shortening in laminopathic dilated cardiomyopathy
Laminopathies are a group of rare disease due to mutations in the LMNA gene, which is crucial for nuclear integrity and cellular rigidity. Depending on the mutation, the disease manifests in striated muscles, adipose tissues, nerves, and the heart. Although many laminopathic patients exhibit accelerated aging syndromes, the connection as to why loss of LMNA drives aging remains unknown. Herein, we present evidence that cardiomyocytes from laminopathic heart sections exhibit shortened telomeres. Patient derived hiPSC-CMs we observed LMNA mutation results in myocardial enlargement and altered contractility in cardiomyocytes. Further, laminopathic murine cardiomyocytes recapitulates telomere attrition phenotype.
Journal Article
Insights into single hiPSC-derived cardiomyocyte phenotypes and maturation using ConTraX, an efficient pipeline for tracking contractile dynamics
Abstract Cardiomyocytes derived from human induced pluripotent stem cells (hiPSC-CMs) are powerful in-vitro models to study the mechanisms underlying cardiomyopathies and cardiotoxicity. To understand how cellular mechanisms affect the heart, it is crucial to quantify the contractile function in single hiPSC-CMs over time, however, such measurements remain demanding and low-throughput, and are too seldom considered. We developed an open-access, versatile, streamlined, and highly automated pipeline to address these challenges and enable quantitative tracking of the contractile dynamics of single hiPSC- CMs over time: ConTraX. Three interlocking software modules enable: (i) parameter-based localization and selection of single hiPSC-CMs; (ii) automated video acquisition of >200 cells/hour; and (iii) streamlined measurements of the contractile parameters via traction force microscopy. Using ConTraX, we analyzed >2,753 hiPSC-CMs over time under orthogonal experimental conditions in terms of culture media and substrate stiffnesses. Using undirected high-dimensional clustering, we dissected the complex diversity of contractile phenotypes in hiPSC-CM populations and revealed converging maturation patterns. Our modular ConTraX pipeline empowers biologists with a potent quantitative analytic tool applicable to the development of cardiac therapies. Competing Interest Statement The authors have declared no competing interest. Footnotes * https://github.com/MicrosystemsLab/ContraX * List of Abbreviations hiPSC Human-induced pluripotent stem cell CM Cardiomyocyte TFM Traction force microscopy PIV Particle image velocimetry DIC Digital image correlation FTTC Fourier transform traction cytometry GUI Graphical User Interface
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