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"Keller gordon" cardiac

Boyang Zhang, Miles Montgomery, M Dean Chamberlain, Shinichiro Ogawa, Anastasia Korolj, Aric Pahnke, Laura A Wells, Stéphane Massé, Jihye Kim, Lewis Reis, Abdul Momen, Sara S Nunes, Aaron R Wheeler, Kumaraswamy Nanthakumar, Gordon Keller, Michael V Sefton, Milica Radisic
We report the fabrication of a scaffold (hereafter referred to as AngioChip) that supports the assembly of parenchymal cells on a mechanically tunable matrix surrounding a perfusable, branched, three-dimensional microchannel network coated with endothelial cells. The design of AngioChip decouples the material choices for the engineered vessel network and for cell seeding in the parenchyma, enabling extensive remodelling while maintaining an open-vessel lumen. The incorporation of nanopores and micro-holes in the vessel walls enhances permeability, and permits intercellular crosstalk and extravasation of monocytes and endothelial cells on biomolecular stimulation...
June 2016: Nature Materials
Sarah Fernandes, James J H Chong, Sharon L Paige, Mineo Iwata, Beverly Torok-Storb, Gordon Keller, Hans Reinecke, Charles E Murry
Cardiomyocytes derived from human embryonic stem cells (hESC-CMs) can improve the contractility of injured hearts.We hypothesized that mesodermal cardiovascular progenitors (hESC-CVPs), capable of generating vascular cells in addition to cardiomyocytes, would provide superior repair by contributing to multiple components of myocardium. We performed a head-to-head comparison of hESC-CMs and hESC-CVPs and compared these with the most commonly used clinical cell type, human bone marrow mononuclear cells (hBMMNCs)...
November 10, 2015: Stem Cell Reports
Parveen Sharma, Cynthia Abbasi, Savo Lazic, Allen C T Teng, Dingyan Wang, Nicole Dubois, Vladimir Ignatchenko, Victoria Wong, Jun Liu, Toshiyuki Araki, Malte Tiburcy, Cameron Ackerley, Wolfram H Zimmermann, Robert Hamilton, Yu Sun, Peter P Liu, Gordon Keller, Igor Stagljar, Ian C Scott, Thomas Kislinger, Anthony O Gramolini
Membrane proteins are crucial to heart function and development. Here we combine cationic silica-bead coating with shotgun proteomics to enrich for and identify plasma membrane-associated proteins from primary mouse neonatal and human fetal ventricular cardiomyocytes. We identify Tmem65 as a cardiac-enriched, intercalated disc protein that increases during development in both mouse and human hearts. Functional analysis of Tmem65 both in vitro using lentiviral shRNA-mediated knockdown in mouse cardiomyocytes and in vivo using morpholino-based knockdown in zebrafish show marked alterations in gap junction function and cardiac morphology...
2015: Nature Communications
Jia-Ling Ruan, Nathaniel L Tulloch, Mark Saiget, Sharon L Paige, Maria V Razumova, Michael Regnier, Kelvin Chan Tung, Gordon Keller, Lil Pabon, Hans Reinecke, Charles E Murry
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, and endothelial cells. Because the heart develops from progenitors in 3D under constant mechanical load, we sought to test the effects of a 3D microenvironment and mechanical stress on differentiation and maturation of human cardiovascular progenitors into myocardial tissue. Progenitors were derived from embryonic stem cells, cast into collagen hydrogels, and left unstressed or subjected to static or cyclic mechanical stress...
July 2015: Stem Cells
Andrew B J Prowse, Nicholas E Timmins, Terrence M Yau, Ren-Ke Li, Richard D Weisel, Gordon Keller, Peter W Zandstra
Despite advances in coronary artery disease treatment and prevention, myocardial damage due to acute myocardial infarction (MI) remains a major cause of morbidity and mortality in the population. Cell-based clinical trials to treat MI have focused on cells derived from the bone marrow or those potentially possessing functional similarities such as skeletal myoblasts or cardiac progenitors isolated from heart biopsies. Any benefits provided by these cells in improving heart function, left ventricular ejection fraction, or extending life expectancy after MI have been credited mostly to paracrine effects...
November 2014: Canadian Journal of Cardiology
Alec D Witty, Anton Mihic, Roger Y Tam, Stephanie A Fisher, Alexander Mikryukov, Molly S Shoichet, Ren-Ke Li, Steven J Kattman, Gordon Keller
The epicardium supports cardiomyocyte proliferation early in development and provides fibroblasts and vascular smooth muscle cells to the developing heart. The epicardium has been shown to play an important role during tissue remodeling after cardiac injury, making access to this cell lineage necessary for the study of regenerative medicine. Here we describe the generation of epicardial lineage cells from human pluripotent stem cells by stage-specific activation of the BMP and WNT signaling pathways. These cells display morphological characteristics and express markers of the epicardial lineage, including the transcription factors WT1 and TBX18 and the retinoic acid-producing enzyme ALDH1A2...
October 2014: Nature Biotechnology
Anton Mihic, Jiao Li, Yasuo Miyagi, Mark Gagliardi, Shu-Hong Li, Jean Zu, Richard D Weisel, Gordon Keller, Ren-Ke Li
The goal of cardiac tissue engineering is to restore function to the damaged myocardium with regenerative constructs. Human embryonic stem cell-derived cardiomyocytes (hESC-CMs) can produce viable, contractile, three-dimensional grafts that function in vivo. We sought to enhance the viability and functional maturation of cardiac tissue constructs by cyclical stretch. hESC-CMs seeded onto gelatin-based scaffolds underwent cyclical stretching. Histological analysis demonstrated a greater proportion of cardiac troponin T-expressing cells in stretched than non-stretched constructs, and flow sorting demonstrated a higher proportion of cardiomyocytes...
March 2014: Biomaterials
Yun Xiao, Boyang Zhang, Haijiao Liu, Jason W Miklas, Mark Gagliardi, Aric Pahnke, Nimalan Thavandiran, Yu Sun, Craig Simmons, Gordon Keller, Milica Radisic
Tissue engineering enables the generation of three-dimensional (3D) functional cardiac tissue for pre-clinical testing in vitro, which is critical for new drug development. However, current tissue engineering methods poorly recapitulate the architecture of oriented cardiac bundles with supporting capillaries. In this study, we designed a microfabricated bioreactor to generate 3D micro-tissues, termed biowires, using both primary neonatal rat cardiomyocytes and human embryonic stem cell (hESC) derived cardiomyocytes...
March 7, 2014: Lab on a Chip
Nimalan Thavandiran, Nicole Dubois, Alexander Mikryukov, Stéphane Massé, Bogdan Beca, Craig A Simmons, Vikram S Deshpande, J Patrick McGarry, Christopher S Chen, Kumaraswamy Nanthakumar, Gordon M Keller, Milica Radisic, Peter W Zandstra
Access to robust and information-rich human cardiac tissue models would accelerate drug-based strategies for treating heart disease. Despite significant effort, the generation of high-fidelity adult-like human cardiac tissue analogs remains challenging. We used computational modeling of tissue contraction and assembly mechanics in conjunction with microfabricated constraints to guide the design of aligned and functional 3D human pluripotent stem cell (hPSC)-derived cardiac microtissues that we term cardiac microwires (CMWs)...
December 3, 2013: Proceedings of the National Academy of Sciences of the United States of America
Naila Gaber, Mark Gagliardi, Pranali Patel, Caroline Kinnear, Cindy Zhang, David Chitayat, Patrick Shannon, Edgar Jaeggi, Uri Tabori, Gordon Keller, Seema Mital
Hypoplastic left heart syndrome (HLHS) is a severe cardiac malformation characterized by left ventricle (LV) hypoplasia and abnormal LV perfusion and oxygenation. We studied hypoxia-associated injury in fetal HLHS and human pluripotent stem cells during cardiac differentiation to assess the effect of microenvironmental perturbations on fetal cardiac reprogramming. We studied LV myocardial samples from 32 HLHS and 17 structurally normal midgestation fetuses. Compared with controls, the LV in fetal HLHS samples had higher nuclear expression of hypoxia-inducible factor-1α but lower angiogenic growth factor expression, higher expression of oncogenes and transforming growth factor (TGF)-β1, more DNA damage and senescence with cell cycle arrest, fewer cardiac progenitors, myocytes and endothelial lineages, and increased myofibroblast population (P < 0...
September 2013: American Journal of Pathology
Sara S Nunes, Jason W Miklas, Jie Liu, Roozbeh Aschar-Sobbi, Yun Xiao, Boyang Zhang, Jiahua Jiang, Stéphane Massé, Mark Gagliardi, Anne Hsieh, Nimalan Thavandiran, Michael A Laflamme, Kumaraswamy Nanthakumar, Gil J Gross, Peter H Backx, Gordon Keller, Milica Radisic
Directed differentiation protocols enable derivation of cardiomyocytes from human pluripotent stem cells (hPSCs) and permit engineering of human myocardium in vitro. However, hPSC-derived cardiomyocytes are reflective of very early human development, limiting their utility in the generation of in vitro models of mature myocardium. Here we describe a platform that combines three-dimensional cell cultivation with electrical stimulation to mature hPSC-derived cardiac tissues. We used quantitative structural, molecular and electrophysiological analyses to explain the responses of immature human myocardium to electrical stimulation and pacing...
August 2013: Nature Methods
Michael Didié, Peter Christalla, Michael Rubart, Vijayakumar Muppala, Stephan Döker, Bernhard Unsöld, Ali El-Armouche, Thomas Rau, Thomas Eschenhagen, Alexander P Schwoerer, Heimo Ehmke, Udo Schumacher, Sigrid Fuchs, Claudia Lange, Alexander Becker, Wen Tao, John A Scherschel, Mark H Soonpaa, Tao Yang, Qiong Lin, Martin Zenke, Dong-Wook Han, Hans R Schöler, Cornelia Rudolph, Doris Steinemann, Brigitte Schlegelberger, Steve Kattman, Alec Witty, Gordon Keller, Loren J Field, Wolfram-Hubertus Zimmermann
Uniparental parthenotes are considered an unwanted byproduct of in vitro fertilization. In utero parthenote development is severely compromised by defective organogenesis and in particular by defective cardiogenesis. Although developmentally compromised, apparently pluripotent stem cells can be derived from parthenogenetic blastocysts. Here we hypothesized that nonembryonic parthenogenetic stem cells (PSCs) can be directed toward the cardiac lineage and applied to tissue-engineered heart repair. We first confirmed similar fundamental properties in murine PSCs and embryonic stem cells (ESCs), despite notable differences in genetic (allelic variability) and epigenetic (differential imprinting) characteristics...
March 2013: Journal of Clinical Investigation
Deborah K Lieu, Ji-Dong Fu, Nipavan Chiamvimonvat, Kelvin Chan Tung, Gregory P McNerney, Thomas Huser, Gordon Keller, Chi-Wing Kong, Ronald A Li
BACKGROUND: Human embryonic stem cells (hESCs) can be efficiently and reproducibly directed into cardiomyocytes (CMs) using stage-specific induction protocols. However, their functional properties and suitability for clinical and other applications have not been evaluated. METHODS AND RESULTS: Here we showed that CMs derived from multiple pluripotent human stem cell lines (hESC: H1, HES2) and types (induced pluripotent stem cell) using different in vitro differentiation protocols (embryoid body formation, endodermal induction, directed differentiation) commonly displayed immature, proarrhythmic action potential properties such as high degree of automaticity, depolarized resting membrane potential, Phase 4- depolarization, and delayed after-depolarization...
February 2013: Circulation. Arrhythmia and Electrophysiology
Cecile Terrenoire, Kai Wang, Kelvin W Chan Tung, Wendy K Chung, Robert H Pass, Jonathan T Lu, Jyh-Chang Jean, Amel Omari, Kevin J Sampson, Darrell N Kotton, Gordon Keller, Robert S Kass
Understanding the basis for differential responses to drug therapies remains a challenge despite advances in genetics and genomics. Induced pluripotent stem cells (iPSCs) offer an unprecedented opportunity to investigate the pharmacology of disease processes in therapeutically and genetically relevant primary cell types in vitro and to interweave clinical and basic molecular data. We report here the derivation of iPSCs from a long QT syndrome patient with complex genetics. The proband was found to have a de novo SCN5A LQT-3 mutation (F1473C) and a polymorphism (K897T) in KCNH2, the gene for LQT-2...
January 2013: Journal of General Physiology
Omar El-Mounayri, Anton Mihic, Eric A Shikatani, Mark Gagliardi, Sarah K Steinbach, Nicole Dubois, Ralph Dacosta, Ren-Ke Li, Gordon Keller, Mansoor Husain
AIMS: Despite the diverse developmental origins of vascular smooth muscle cells (VSMCs), recent attempts to generate VSMCs from human embryonic stem cells (hESCs) differentiated along various lineages did not yield distinct cell phenotypes. The aim of this study was to derive and characterize functional coronary-like VSMCs from hESCs using serum-free cardiac-directed differentiation. METHODS AND RESULTS: Embryoid bodies (EBs) from three pluripotent stem cell lines subjected to cardiac-directed differentiation in defined media were characterized over 30 days for VSMC-specific gene expression by qRT-PCR, immunofluorescence microscopy and fluorescence-activated cell sorting (FACS)...
April 1, 2013: Cardiovascular Research
Elena Serena, Elisa Cimetta, Susi Zatti, Tania Zaglia, Monica Zagallo, Gordon Keller, Nicola Elvassore
INTRODUCTION: The heart is one of the least regenerative organs in the body and any major insult can result in a significant loss of heart cells. The development of an in vitro-based cardiac tissue could be of paramount importance for many aspects of the cardiology research. In this context, we developed an in vitro assay based on human cardiomyocytes (hCMs) and ad hoc micro-technologies, suitable for several applications: from pharmacological analysis to physio-phatological studies on transplantable hCMs...
2012: PloS One
Joseph A Wamstad, Jeffrey M Alexander, Rebecca M Truty, Avanti Shrikumar, Fugen Li, Kirsten E Eilertson, Huiming Ding, John N Wylie, Alexander R Pico, John A Capra, Genevieve Erwin, Steven J Kattman, Gordon M Keller, Deepak Srivastava, Stuart S Levine, Katherine S Pollard, Alisha K Holloway, Laurie A Boyer, Benoit G Bruneau
Heart development is exquisitely sensitive to the precise temporal regulation of thousands of genes that govern developmental decisions during differentiation. However, we currently lack a detailed understanding of how chromatin and gene expression patterns are coordinated during developmental transitions in the cardiac lineage. Here, we interrogated the transcriptome and several histone modifications across the genome during defined stages of cardiac differentiation. We find distinct chromatin patterns that are coordinated with stage-specific expression of functionally related genes, including many human disease-associated genes...
September 28, 2012: Cell
Sharon L Paige, Sean Thomas, Cristi L Stoick-Cooper, Hao Wang, Lisa Maves, Richard Sandstrom, Lil Pabon, Hans Reinecke, Gabriel Pratt, Gordon Keller, Randall T Moon, John Stamatoyannopoulos, Charles E Murry
Directed differentiation of human embryonic stem cells (ESCs) into cardiovascular cells provides a model for studying molecular mechanisms of human cardiovascular development. Although it is known that chromatin modification patterns in ESCs differ markedly from those in lineage-committed progenitors and differentiated cells, the temporal dynamics of chromatin alterations during differentiation along a defined lineage have not been studied. We show that differentiation of human ESCs into cardiovascular cells is accompanied by programmed temporal alterations in chromatin structure that distinguish key regulators of cardiovascular development from other genes...
September 28, 2012: Cell
Paul W Burridge, Gordon Keller, Joseph D Gold, Joseph C Wu
Cardiovascular disease is a leading cause of death worldwide. The limited capability of heart tissue to regenerate has prompted methodological developments for creating de novo cardiomyocytes, both in vitro and in vivo. Beyond uses in cell replacement therapy, patient-specific cardiomyocytes may find applications in drug testing, drug discovery, and disease modeling. Recently, approaches for generating cardiomyocytes have expanded to encompass three major sources of starting cells: human pluripotent stem cells (hPSCs), adult heart-derived cardiac progenitor cells (CPCs), and reprogrammed fibroblasts...
January 6, 2012: Cell Stem Cell
Masayoshi Ishida, Omar El-Mounayri, Steven Kattman, Peter Zandstra, Hiroshi Sakamoto, Minetaro Ogawa, Gordon Keller, Mansoor Husain
RATIONALE: c-myb null (knockout) embryonic stem cells (ESC) can differentiate into cardiomyocytes but not contractile smooth muscle cells (SMC) in embryoid bodies (EB). OBJECTIVE: To define the role of c-Myb in SMC differentiation from ESC. METHODS AND RESULTS: In wild-type (WT) EB, high c-Myb levels on days 0-2 of differentiation undergo ubiquitin-mediated proteosomal degradation on days 2.5-3, resurging on days 4-6, without changing c-myb mRNA levels...
January 20, 2012: Circulation Research
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