6 results on '"Fugate, James A."'
Search Results
2. Human embryonic stem cell-derived cardiomyocytes restore function in infarcted hearts of non-human primates.
- Author
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Liu YW, Chen B, Yang X, Fugate JA, Kalucki FA, Futakuchi-Tsuchida A, Couture L, Vogel KW, Astley CA, Baldessari A, Ogle J, Don CW, Steinberg ZL, Seslar SP, Tuck SA, Tsuchida H, Naumova AV, Dupras SK, Lyu MS, Lee J, Hailey DW, Reinecke H, Pabon L, Fryer BH, MacLellan WR, Thies RS, and Murry CE
- Subjects
- Animals, Cryopreservation, Disease Models, Animal, Humans, Macaca, Myocardial Infarction pathology, Myocardium pathology, Myocytes, Cardiac cytology, Pluripotent Stem Cells transplantation, Primates, Cell Differentiation genetics, Human Embryonic Stem Cells transplantation, Myocardial Infarction therapy, Myocytes, Cardiac transplantation
- Abstract
Pluripotent stem cell-derived cardiomyocyte grafts can remuscularize substantial amounts of infarcted myocardium and beat in synchrony with the heart, but in some settings cause ventricular arrhythmias. It is unknown whether human cardiomyocytes can restore cardiac function in a physiologically relevant large animal model. Here we show that transplantation of ∼750 million cryopreserved human embryonic stem cell-derived cardiomyocytes (hESC-CMs) enhances cardiac function in macaque monkeys with large myocardial infarctions. One month after hESC-CM transplantation, global left ventricular ejection fraction improved 10.6 ± 0.9% vs. 2.5 ± 0.8% in controls, and by 3 months there was an additional 12.4% improvement in treated vs. a 3.5% decline in controls. Grafts averaged 11.6% of infarct size, formed electromechanical junctions with the host heart, and by 3 months contained ∼99% ventricular myocytes. A subset of animals experienced graft-associated ventricular arrhythmias, shown by electrical mapping to originate from a point-source acting as an ectopic pacemaker. Our data demonstrate that remuscularization of the infarcted macaque heart with human myocardium provides durable improvement in left ventricular function.
- Published
- 2018
- Full Text
- View/download PDF
3. Human embryonic-stem-cell-derived cardiomyocytes regenerate non-human primate hearts.
- Author
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Chong JJ, Yang X, Don CW, Minami E, Liu YW, Weyers JJ, Mahoney WM, Van Biber B, Cook SM, Palpant NJ, Gantz JA, Fugate JA, Muskheli V, Gough GM, Vogel KW, Astley CA, Hotchkiss CE, Baldessari A, Pabon L, Reinecke H, Gill EA, Nelson V, Kiem HP, Laflamme MA, and Murry CE
- Subjects
- Animals, Arrhythmias, Cardiac physiopathology, Calcium metabolism, Cell Survival, Coronary Vessels physiology, Cryopreservation, Disease Models, Animal, Electrocardiography, Humans, Macaca nemestrina, Male, Mice, Regenerative Medicine methods, Embryonic Stem Cells cytology, Heart, Myocardial Infarction pathology, Myocardial Infarction therapy, Myocytes, Cardiac cytology, Regeneration
- Abstract
Pluripotent stem cells provide a potential solution to current epidemic rates of heart failure by providing human cardiomyocytes to support heart regeneration. Studies of human embryonic-stem-cell-derived cardiomyocytes (hESC-CMs) in small-animal models have shown favourable effects of this treatment. However, it remains unknown whether clinical-scale hESC-CM transplantation is feasible, safe or can provide sufficient myocardial regeneration. Here we show that hESC-CMs can be produced at a clinical scale (more than one billion cells per batch) and cryopreserved with good viability. Using a non-human primate model of myocardial ischaemia followed by reperfusion, we show that cryopreservation and intra-myocardial delivery of one billion hESC-CMs generates extensive remuscularization of the infarcted heart. The hESC-CMs showed progressive but incomplete maturation over a 3-month period. Grafts were perfused by host vasculature, and electromechanical junctions between graft and host myocytes were present within 2 weeks of engraftment. Importantly, grafts showed regular calcium transients that were synchronized to the host electrocardiogram, indicating electromechanical coupling. In contrast to small-animal models, non-fatal ventricular arrhythmias were observed in hESC-CM-engrafted primates. Thus, hESC-CMs can remuscularize substantial amounts of the infarcted monkey heart. Comparable remuscularization of a human heart should be possible, but potential arrhythmic complications need to be overcome.
- Published
- 2014
- Full Text
- View/download PDF
4. Dystrophin-deficient cardiomyocytes derived from human urine: new biologic reagents for drug discovery.
- Author
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Guan X, Mack DL, Moreno CM, Strande JL, Mathieu J, Shi Y, Markert CD, Wang Z, Liu G, Lawlor MW, Moorefield EC, Jones TN, Fugate JA, Furth ME, Murry CE, Ruohola-Baker H, Zhang Y, Santana LF, and Childers MK
- Subjects
- Adult, Animals, Case-Control Studies, Cell Differentiation physiology, Cells, Cultured, Drug Discovery, Female, Humans, Kruppel-Like Factor 4, Kruppel-Like Transcription Factors biosynthesis, Kruppel-Like Transcription Factors urine, Male, Mice, Mice, Inbred NOD, Mice, SCID, Myocytes, Cardiac cytology, Proto-Oncogene Proteins c-myc biosynthesis, Proto-Oncogene Proteins c-myc urine, Telomerase urine, Young Adult, Dystrophin deficiency, Induced Pluripotent Stem Cells pathology, Muscular Dystrophy, Duchenne pathology, Muscular Dystrophy, Duchenne urine, Myocytes, Cardiac metabolism, Myocytes, Cardiac pathology
- Abstract
The ability to extract somatic cells from a patient and reprogram them to pluripotency opens up new possibilities for personalized medicine. Induced pluripotent stem cells (iPSCs) have been employed to generate beating cardiomyocytes from a patient's skin or blood cells. Here, iPSC methods were used to generate cardiomyocytes starting from the urine of a patient with Duchenne muscular dystrophy (DMD). Urine was chosen as a starting material because it contains adult stem cells called urine-derived stem cells (USCs). USCs express the canonical reprogramming factors c-myc and klf4, and possess high telomerase activity. Pluripotency of urine-derived iPSC clones was confirmed by immunocytochemistry, RT-PCR and teratoma formation. Urine-derived iPSC clones generated from healthy volunteers and a DMD patient were differentiated into beating cardiomyocytes using a series of small molecules in monolayer culture. Results indicate that cardiomyocytes retain the DMD patient's dystrophin mutation. Physiological assays suggest that dystrophin-deficient cardiomyocytes possess phenotypic differences from normal cardiomyocytes. These results demonstrate the feasibility of generating cardiomyocytes from a urine sample and that urine-derived cardiomyocytes retain characteristic features that might be further exploited for mechanistic studies and drug discovery., (Copyright © 2013. Published by Elsevier B.V.)
- Published
- 2014
- Full Text
- View/download PDF
5. Proangiogenic scaffolds as functional templates for cardiac tissue engineering.
- Author
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Madden LR, Mortisen DJ, Sussman EM, Dupras SK, Fugate JA, Cuy JL, Hauch KD, Laflamme MA, Murry CE, and Ratner BD
- Subjects
- Animals, Cell Count, Chick Embryo, Humans, Hydrogels, Methacrylates, Microscopy, Electron, Scanning, Polyhydroxyethyl Methacrylate, Rats, Rats, Nude, Rats, Sprague-Dawley, Ventricular Myosins metabolism, Heart, Myocytes, Cardiac cytology, Myocytes, Cardiac physiology, Neovascularization, Physiologic, Tissue Engineering methods, Tissue Scaffolds
- Abstract
We demonstrate here a cardiac tissue-engineering strategy addressing multicellular organization, integration into host myocardium, and directional cues to reconstruct the functional architecture of heart muscle. Microtemplating is used to shape poly(2-hydroxyethyl methacrylate-co-methacrylic acid) hydrogel into a tissue-engineering scaffold with architectures driving heart tissue integration. The construct contains parallel channels to organize cardiomyocyte bundles, supported by micrometer-sized, spherical, interconnected pores that enhance angiogenesis while reducing scarring. Surface-modified scaffolds were seeded with human ES cell-derived cardiomyocytes and cultured in vitro. Cardiomyocytes survived and proliferated for 2 wk in scaffolds, reaching adult heart densities. Cardiac implantation of acellular scaffolds with pore diameters of 30-40 microm showed angiogenesis and reduced fibrotic response, coinciding with a shift in macrophage phenotype toward the M2 state. This work establishes a foundation for spatially controlled cardiac tissue engineering by providing discrete compartments for cardiomyocytes and stroma in a scaffold that enhances vascularization and integration while controlling the inflammatory response.
- Published
- 2010
- Full Text
- View/download PDF
6. Cardiomyocytes derived from human embryonic stem cells in pro-survival factors enhance function of infarcted rat hearts.
- Author
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Laflamme MA, Chen KY, Naumova AV, Muskheli V, Fugate JA, Dupras SK, Reinecke H, Xu C, Hassanipour M, Police S, O'Sullivan C, Collins L, Chen Y, Minami E, Gill EA, Ueno S, Yuan C, Gold J, and Murry CE
- Subjects
- Animals, Cell Differentiation, Cell Movement, Cell Survival, Echocardiography, Heart Ventricles metabolism, Humans, Magnetic Resonance Imaging, Male, Myocytes, Cardiac transplantation, Rats, Rats, Sprague-Dawley, Embryonic Stem Cells cytology, Graft Survival, Myocardial Infarction physiopathology, Myocardial Infarction therapy, Myocardium pathology, Myocytes, Cardiac cytology
- Abstract
Cardiomyocytes derived from human embryonic stem (hES) cells potentially offer large numbers of cells to facilitate repair of the infarcted heart. However, this approach has been limited by inefficient differentiation of hES cells into cardiomyocytes, insufficient purity of cardiomyocyte preparations and poor survival of hES cell-derived myocytes after transplantation. Seeking to overcome these challenges, we generated highly purified human cardiomyocytes using a readily scalable system for directed differentiation that relies on activin A and BMP4. We then identified a cocktail of pro-survival factors that limits cardiomyocyte death after transplantation. These techniques enabled consistent formation of myocardial grafts in the infarcted rat heart. The engrafted human myocardium attenuated ventricular dilation and preserved regional and global contractile function after myocardial infarction compared with controls receiving noncardiac hES cell derivatives or vehicle. The ability of hES cell-derived cardiomyocytes to partially remuscularize myocardial infarcts and attenuate heart failure encourages their study under conditions that closely match human disease.
- Published
- 2007
- Full Text
- View/download PDF
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