A5077720958- Cardiomyopathy and Myosin Studies
- Cardiovascular Effects of Exercise
- Muscle Physiology and Disorders
- Cardiovascular Function and Risk Factors
- Tissue Engineering and Regenerative Medicine
- Force Microscopy Techniques and Applications
- Cellular Mechanics and Interactions
- Pluripotent Stem Cells Research
- Viral Infections and Immunology Research
- Cardiac electrophysiology and arrhythmias
- Congenital heart defects research
- CRISPR and Genetic Engineering
- Electrospun Nanofibers in Biomedical Applications
- Ion channel regulation and function
- Neurogenetic and Muscular Disorders Research
- RNA and protein synthesis mechanisms
- Muscle activation and electromyography studies
- Signaling Pathways in Disease
- Mitochondrial Function and Pathology
- RNA Research and Splicing
- Neuroscience and Neural Engineering
- Fuel Cells and Related Materials
- 3D Printing in Biomedical Research
- Advanced MRI Techniques and Applications
- Advanced Sensor and Energy Harvesting Materials
University of Washington
2016-2025
California Institute for Regenerative Medicine
2014-2024
Institute for Stem Cell Biology and Regenerative Medicine
2024
Center for Translational Molecular Medicine
2024
City University of Seattle
2024
Bioengineering Center
2024
Seattle University
1999-2023
Washington Center
2019-2023
CHU Dinant Godinne UCL Namur
2023
Institute of Translational Health Sciences
2021
Despite preclinical studies demonstrating the functional benefit of transplanting human pluripotent stem cell-derived cardiomyocytes (PSC-CMs) into damaged myocardium, ability these immature cells to adopt a more adult-like cardiomyocyte (CM) phenotype remains uncertain. To address this issue, we tested hypothesis that prolonged in vitro culture embryonic cell (hESC)- and induced (hiPSC)-derived CMs would result maturation their structural contractile properties phenotype. Compared...
Rationale: The developing heart requires both mechanical load and vascularization to reach its proper size, yet the regulation of human growth by these processes is poorly understood. Objective: We seek elucidate responses immature myocardium using tissue engineering approaches. Methods Results: Using embryonic stem cell induced pluripotent cell–derived cardiomyocytes in a 3-dimensional collagen matrix, we show that uniaxial stress conditioning promotes 2-fold increases cardiomyocyte matrix...
Success of human myocardial tissue engineering for cardiac repair has been limited by adverse effects scaffold materials, necrosis at the core, and poor survival after transplantation due to ischemic injury. Here, we report development scaffold-free prevascularized heart that survives in vivo integrates with host coronary circulation. Human embryonic stem cells (hESCs) were differentiated cardiomyocytes using activin A BMP-4 then placed into suspension on a rotating orbital shaker create...
Tissue engineering enables the generation of functional human cardiac tissue with cells derived in vitro combination biocompatible materials. Human-induced pluripotent stem cell-derived cardiomyocytes provide a cell source for engineering; however, their immaturity limits potential applications. Here we sought to study effect mechanical conditioning and electric pacing on maturation human-induced tissues.Cardiomyocytes from were used generate collagen-based bioengineered tissue. Engineered...
Understanding the phenotypic development of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) is a prerequisite to advancing regenerative cardiac therapy, disease modeling, and drug screening applications. Lack consistent hiPSC-CM in vitro data can be largely attributed inability conventional culture methods mimic structural, biochemical, mechanical aspects myocardial niche accurately. Here, we present nanogrid array comprised nanogrooved topographies, with groove widths...
Increased fatty acid oxidation (FAO) has long been considered a culprit in the development of obesity/diabetes mellitus-induced cardiomyopathy. However, enhancing cardiac FAO by removing inhibitory mechanism long-chain transport into mitochondria via deletion acetyl coenzyme A carboxylase 2 (ACC2) does not cause cardiomyopathy nonobese mice, suggesting that high is distinct from lipotoxicity. We hypothesize pathology-associated obesity attributable to imbalance supply and oxidation. Thus, we...
Recent advances in pluripotent stem cell biology and directed differentiation have identified a population of human cardiovascular progenitors that give rise to cardiomyocytes, smooth muscle, endothelial cells. Because the heart develops from 3D under constant mechanical load, we sought test effects microenvironment stress on maturation into myocardial tissue. Progenitors were derived embryonic cells, cast collagen hydrogels, left unstressed or subjected static cyclic stress. Compared 2D...
Classic interpretations of the striated muscle length–tension curve focus on how force varies with overlap thin (actin) and thick (myosin) filaments. New models sarcomere geometry experiments skinned synchronous insect flight suggest that changes in radial distance between actin myosin filaments, filament lattice spacing, are responsible for 20% 50% change seen lengths 1.4 3.4 µm. Thus, spacing is a significant regulator, increasing slope muscle's force–length dependence.
Abstract Even in healthy aging, cardiac morbidity and mortality increase with age both mice humans. These effects include a decline diastolic function, left ventricular hypertrophy, metabolic substrate shifts, alterations the proteome. Previous work from our laboratory indicated that short‐term (10‐week) treatment rapamycin, an mTORC1 inhibitor, improved measures of these age‐related changes. In this report, we demonstrate rapamycin‐dependent improvement function is highly persistent, while...
A novel myosin heavy chain 7 mutation (E848G) identified in a familial cardiomyopathy was studied patient-specific induced pluripotent stem cell–derived cardiomyocytes. The cardiomyopathic human cardiomyocytes exhibited reduced contractile function as single cells and engineered heart tissues, genome-edited isogenic confirmed the pathogenic nature of E848G mutation. Reduced contractility may result from impaired interaction between cardiac binding protein C.
Muscle myosin heads, in the absence of actin, have been shown to exist two states, relaxed (turnover ∼0.05 s−1) and super-relaxed states (SRX, 0.005 using a simple fluorescent ATP chase assay (Hooijman, P. et al (2011) Biophys. J. 100, 1969–1976). Studies normally used purified proteins, filaments, or muscle fibers. Here we use myofibrils, which retain most ancillary proteins 3-D architecture can be with rapid mixing methods. Recording timescales from 0.1 1000 s provides precise measure...
Contraction in striated muscle is initiated by calcium binding to troponin complexes, but it now understood that dynamic transition of myosin between resting, ordered OFF states on thick filaments and active, disordered ON can bind thin critical regulating contractility. These structural transitions are widely assumed correspond from the biochemically defined, energy-sparing, super-relaxed (SRX) state higher ATPase disordered-relaxed (DRX) state. Here we examined effect 2’-deoxy-ATP (dATP),...
How does neural activity drive muscles to produce behavior? The recent development of genetic lines in Hydra that allow complete calcium imaging both neuronal and muscle activity, as well systematic machine learning quantification behaviors, makes this small cnidarian an ideal model system understand the transformation from firing body movements. To achieve this, we have built a neuromechanical ’s fluid-filled hydrostatic skeleton, showing how by activates distinct patterns column...
Changes in thin filament structure induced by Ca(2+) binding to troponin and subsequent strong cross-bridge regulate additional attachment, force development, dependence of on sarcomere length skeletal cardiac muscle. Variations activation properties account for functional differences between these muscle types.
Myosin binding protein-C (MyBP-C) is a thick-filament protein whose precise function within the sarcomere not known. However, recent evidence from cMyBP-C knock-out mice that lack MyBP-C in heart suggest normally slows cross-bridge cycling rates and reduces myocyte power output. To investigate possible mechanisms by which limits kinetics we assessed effects of recombinant N-terminal domains on ability heavy meromyosin (HMM) to support movement actin filaments using vitro motility assays....
H ypertrophic cardiomyopathy (HCM) is a myocardial dis- order characterized by left ventricular (LV) hypertrophy without dilatation and apparent cause (ie, it occurs in the absence of severe hypertension, aortic stenosis, or other cardiac systemic diseases that might LV hypertrophy).2][3][4][5][6][7][8] HCM leading sudden death young people leads to significant disability survivors.It caused mutations genes encode components sarcomere.Cardiomyocyte hypertrophy, myocyte disarray, interstitial...
In muscle, force emerges from myosin binding with actin (forming a cross-bridge). This actomyosin depends upon myofilament geometry, kinetics of thin-filament Ca(2+) activation, and cross-bridge cycling. Binding occurs within compliant network protein filaments where there is mechanical coupling between myosins along the thick-filament backbone monomers thin filament. Such precludes using ordinary differential equation models when examining effects lattice kinetics, or compliance on...