Engineered heart tissues and induced pluripotent stem cells: Macro- and microstructures for disease modeling, drug screening, and translational studies.

Engineered heart tissue has emerged as a personalized platform for drug screening. With the advent of induced pluripotent stem cell (iPSC) technology, patient-specific stem cells can be developed and expanded into an indefinite source of cells. Subsequent developments in cardiovascular biology have led to efficient differentiation of cardiomyocytes, the force-producing cells of the heart. iPSC-derived cardiomyocytes (iPSC-CMs) have provided potentially limitless quantities of well-characterized, healthy, and disease-specific CMs, which in turn has enabled and driven the generation and scale-up of human physiological and disease-relevant engineered heart tissues. The combined technologies of engineered heart tissue and iPSC-CMs are being used to study diseases and to test drugs, and in the process, have advanced the field of cardiovascular tissue engineering into the field of precision medicine. In this review, we will discuss current developments in engineered heart tissue, including iPSC-CMs as a novel cell source. We examine new research directions that have improved the function of engineered heart tissue by using mechanical or electrical conditioning or the incorporation of non-cardiomyocyte stromal cells. Finally, we discuss how engineered heart tissue can evolve into a powerful tool for therapeutic drug testing.

[1]  Charles E. Murry,et al.  Growth of Engineered Human Myocardium With Mechanical Loading and Vascular Coculture , 2011, Circulation research.

[2]  R. Passier,et al.  Human stem cells as a model for cardiac differentiation and disease , 2009, Cellular and Molecular Life Sciences.

[3]  Andreas Hess,et al.  Engineered heart tissue grafts improve systolic and diastolic function in infarcted rat hearts , 2006, Nature Medicine.

[4]  Euan A Ashley,et al.  Abnormal calcium handling properties underlie familial hypertrophic cardiomyopathy pathology in patient-specific induced pluripotent stem cells. , 2013, Cell stem cell.

[5]  Gang Wang,et al.  Modeling the mitochondrial cardiomyopathy of Barth syndrome with iPSC and heart-on-chip technologies , 2014 .

[6]  B. R. Jewell,et al.  Calcium‐ and length‐dependent force production in rat ventricular muscle , 1982, The Journal of physiology.

[7]  Ronald A. Li,et al.  Developmental cues for the maturation of metabolic, electrophysiological and calcium handling properties of human pluripotent stem cell-derived cardiomyocytes , 2014, Stem Cell Research & Therapy.

[8]  P. Burridge,et al.  Characterization of the molecular mechanisms underlying increased ischemic damage in the aldehyde dehydrogenase 2 genetic polymorphism using a human induced pluripotent stem cell model system , 2014, Science Translational Medicine.

[9]  Nenad Bursac,et al.  Tissue-engineered cardiac patch for advanced functional maturation of human ESC-derived cardiomyocytes. , 2013, Biomaterials.

[10]  I. Karakikes,et al.  Human induced pluripotent stem cell-derived cardiomyocytes: insights into molecular, cellular, and functional phenotypes. , 2015, Circulation research.

[11]  Sean P. Palecek,et al.  Functional Cardiomyocytes Derived From Human Induced Pluripotent Stem Cells , 2009, Circulation research.

[12]  Deborah K. Lieu,et al.  Distinct Roles of MicroRNA-1 and -499 in Ventricular Specification and Functional Maturation of Human Embryonic Stem Cell-Derived Cardiomyocytes , 2011, PloS one.

[13]  Euan A. Ashley,et al.  Patient-Specific Induced Pluripotent Stem Cells as a Model for Familial Dilated Cardiomyopathy , 2012, Science Translational Medicine.

[14]  Hiroshi Morita,et al.  The QT syndromes: long and short , 2008, The Lancet.

[15]  B. Munos,et al.  A Call for Sharing: Adapting Pharmaceutical Research to New Realities , 2009, Science Translational Medicine.

[16]  J. Lüdemann,et al.  Existence of the Frank-Starling mechanism in the failing human heart. Investigations on the organ, tissue, and sarcomere levels. , 1996, Circulation.

[17]  J. Ornato,et al.  ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult—Summary Article , 2005 .

[18]  Gordon Keller,et al.  Production of de novo cardiomyocytes: human pluripotent stem cell differentiation and direct reprogramming. , 2012, Cell stem cell.

[19]  P. Alagona,et al.  The worldwide environment of cardiovascular disease: prevalence, diagnosis, therapy, and policy issues: a report from the American College of Cardiology. , 2012, Journal of the American College of Cardiology.

[20]  Gordana Vunjak-Novakovic,et al.  Effects of oxygen on engineered cardiac muscle. , 2002, Biotechnology and bioengineering.

[21]  Sean P. Palecek,et al.  Robust cardiomyocyte differentiation from human pluripotent stem cells via temporal modulation of canonical Wnt signaling , 2012, Proceedings of the National Academy of Sciences.

[22]  P. Nguyen,et al.  Stem cell imaging: from bench to bedside. , 2014, Cell stem cell.

[23]  Michael D. Schneider,et al.  Conduction Slowing and Sudden Arrhythmic Death in Mice With Cardiac-Restricted Inactivation of Connexin43 , 2001, Circulation research.

[24]  Jürgen Hescheler,et al.  Organotypic slice culture from human adult ventricular myocardium. , 2012, Cardiovascular research.

[25]  Mechanism of ventricular defibrillation. The role of tissue geometry in the changes in transmembrane potential in patterned myocyte cultures. , 2000, Circulation.

[26]  R. Dehaan,et al.  Development of Sensitivity to Tetrodotoxin in Beating Chick Embryo Hearts, Single Cells, and Aggregates , 1972, Science.

[27]  R. Stewart,et al.  Induced Pluripotent Stem Cell Lines Derived from Human Somatic Cells , 2007, Science.

[28]  A. Hill,et al.  The relation of length to tension development and heat production on contraction in muscle , 1914, The Journal of physiology.

[29]  J. Valentin,et al.  In vitro models of proarrhythmia , 2008, British journal of pharmacology.

[30]  Amir Lerman,et al.  Drug attrition during pre-clinical and clinical development: understanding and managing drug-induced cardiotoxicity. , 2013, Pharmacology & therapeutics.

[31]  Thomas Rau,et al.  Human Engineered Heart Tissue as a Versatile Tool in Basic Research and Preclinical Toxicology , 2011, PloS one.

[32]  Kumaraswamy Nanthakumar,et al.  Biowire: a New Platform for Maturation of Human Pluripotent Stem Cell Derived Cardiomyocytes Pubmed Central Canada , 2022 .

[33]  C. Mummery,et al.  Induced pluripotent stem cell derived cardiomyocytes as models for cardiac arrhythmias , 2012, Front. Physio..

[34]  F. Waagstein,et al.  Improved exercise hemodynamic status in dilated cardiomyopathy after beta-adrenergic blockade treatment. , 1994, Journal of the American College of Cardiology.

[35]  S. Sheehy,et al.  Quality Metrics for Stem Cell-Derived Cardiac Myocytes , 2014, Stem cell reports.

[36]  M Delmar,et al.  Null Mutation of Connexin43 Causes Slow Propagation of Ventricular Activation in the Late Stages of Mouse Embryonic Development , 2001, Circulation research.

[37]  R J Cohen,et al.  Cardiac muscle tissue engineering : toward an in vitro model for electrophysiological studies , 1999 .

[38]  Jarrett Rosenberg,et al.  Single cell transcriptional profiling reveals heterogeneity of human induced pluripotent stem cells. , 2011, The Journal of clinical investigation.

[39]  Carl-Fredrik Mandenius,et al.  Cardiotoxicity testing using pluripotent stem cell‐derived human cardiomyocytes and state‐of‐the‐art bioanalytics: a review , 2011, Journal of applied toxicology : JAT.

[40]  A. Gillich,et al.  Cardiac Tissue Slice Transplantation as a Model to Assess Tissue-Engineered Graft Thickness, Survival, and Function , 2014, Circulation.

[41]  Megan L. McCain,et al.  Ensembles of engineered cardiac tissues for physiological and pharmacological study: heart on a chip. , 2011, Lab on a chip.

[42]  Malte Tiburcy,et al.  Human Engineered Heart Muscles Engraft and Survive Long Term in a Rodent Myocardial Infarction Model. , 2015, Circulation research.

[43]  Jonathan A. Bernstein,et al.  Using iPS cells to investigate cardiac phenotypes in patients with Timothy Syndrome , 2011, Nature.

[44]  Divya Rajamohan,et al.  Drug evaluation in cardiomyocytes derived from human induced pluripotent stem cells carrying a long QT syndrome type 2 mutation , 2011, European heart journal.

[45]  M. Kay,et al.  Genome editing of isogenic human induced pluripotent stem cells recapitulates long QT phenotype for drug testing. , 2014, Journal of the American College of Cardiology.

[46]  L. Hutchinson,et al.  High drug attrition rates—where are we going wrong? , 2011, Nature Reviews Clinical Oncology.

[47]  Lei Yang,et al.  Patient-specific induced pluripotent stem cell derived models of LEOPARD syndrome , 2010, Nature.

[48]  Luke P. Lee,et al.  Human iPSC-based Cardiac Microphysiological System For Drug Screening Applications , 2015, Scientific Reports.

[49]  W. Zimmermann,et al.  3D engineered heart tissue for replacement therapy , 2002, Basic Research in Cardiology.

[50]  G. Salama,et al.  Optical Imaging of the Heart , 2004, Circulation research.

[51]  Y. Mukohata,et al.  Two possible roles of bacteriorhodopsin; a comparative study of strains of Halobacterium halobium differing in pigmentation. , 1977, Biochemical and biophysical research communications.

[52]  Ido Perlman,et al.  Mechanism of spontaneous excitability in human embryonic stem cell derived cardiomyocytes , 2004, The Journal of physiology.

[53]  Yosuke K. Kurokawa,et al.  Tissue engineering the cardiac microenvironment: Multicellular microphysiological systems for drug screening. , 2016, Advanced drug delivery reviews.

[54]  T. Ichisaka,et al.  Induction of Pluripotent Stem Cells From Adult Human Fibroblasts by Defined Factors , 2008 .

[55]  K. Bendixen,et al.  Physiological function and transplantation of scaffold-free and vascularized human cardiac muscle tissue , 2009, Proceedings of the National Academy of Sciences.

[56]  Praveen Shukla,et al.  Chemically defined generation of human cardiomyocytes , 2014, Nature Methods.

[57]  Thomas Eschenhagen,et al.  Three‐dimensional reconstitution of embryonic cardiomyocytes in a collagen matrix: a new heart muscle model system , 1997, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[58]  Jae Young Lee,et al.  Human induced pluripotent stem cell-based microphysiological tissue models of myocardium and liver for drug development , 2013, Stem Cell Research & Therapy.

[59]  Oscar J. Abilez,et al.  Cardiac optogenetics , 2012, 2012 Annual International Conference of the IEEE Engineering in Medicine and Biology Society.

[60]  Lila R Collins,et al.  Cardiomyocytes derived from human embryonic stem cells in pro-survival factors enhance function of infarcted rat hearts , 2007, Nature Biotechnology.

[61]  Y. Fung A first course in continuum mechanics , 1969 .

[62]  Sang Won Seo,et al.  Corrigendum: A Network Flow-based Analysis of Cognitive Reserve in Normal Ageing and Alzheimer’s Disease , 2015, Scientific Reports.

[63]  Katriina Aalto-Setälä,et al.  Model for long QT syndrome type 2 using human iPS cells demonstrates arrhythmogenic characteristics in cell culture , 2011, Disease Models & Mechanisms.

[64]  Kam W Leong,et al.  Pluripotent stem cell-derived cardiac tissue patch with advanced structure and function. , 2011, Biomaterials.

[65]  Karl-Ludwig Laugwitz,et al.  Patient-specific induced pluripotent stem-cell models for long-QT syndrome. , 2010, New England Journal of Medicine.

[66]  E. Green,et al.  A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome , 1995, Cell.

[67]  Paul W. Burridge,et al.  Human Stem Cells for Modeling Heart Disease and for Drug Discovery , 2014, Science Translational Medicine.

[68]  W. Zimmermann,et al.  Tissue Engineering of a Differentiated Cardiac Muscle Construct , 2002, Circulation research.

[69]  F J Schoen,et al.  Cardiac tissue engineering: cell seeding, cultivation parameters, and tissue construct characterization. , 1999, Biotechnology and bioengineering.

[70]  Thomas Boudou,et al.  A microfabricated platform to measure and manipulate the mechanics of engineered cardiac microtissues. , 2012, Tissue engineering. Part A.

[71]  Philip T Sager,et al.  Finding the rhythm of sudden cardiac death: new opportunities using induced pluripotent stem cell-derived cardiomyocytes. , 2015, Circulation research.

[72]  R. P. Thompson,et al.  Dissociated spatial patterning of gap junctions and cell adhesion junctions during postnatal differentiation of ventricular myocardium. , 1997, Circulation research.

[73]  Lil Pabon,et al.  Engineering Adolescence: Maturation of Human Pluripotent Stem Cell–Derived Cardiomyocytes , 2014, Circulation research.

[74]  Herman H. Vandenburgh,et al.  Maintenance of highly contractile tissue-cultured avian skeletal myotubes in collagen gel , 1988, In Vitro Cellular & Developmental Biology.

[75]  A. Yeung,et al.  Preclinical Derivation and Imaging of Autologously Transplanted Canine Induced Pluripotent Stem Cells* , 2011, The Journal of Biological Chemistry.

[76]  Andreas Hess,et al.  Cardiac Grafting of Engineered Heart Tissue in Syngenic Rats , 2002, Circulation.

[77]  Donald M Bers,et al.  Screening Drug-Induced Arrhythmia Using Human Induced Pluripotent Stem Cell–Derived Cardiomyocytes and Low-Impedance Microelectrode Arrays , 2013, Circulation.

[78]  M. Radisic,et al.  Spatiotemporal tracking of cells in tissue‐engineered cardiac organoids , 2009, Journal of tissue engineering and regenerative medicine.

[79]  P. Burridge,et al.  Chemically Defined Culture and Cardiomyocyte Differentiation of Human Pluripotent Stem Cells , 2015, Current protocols in human genetics.

[80]  Milica Radisic,et al.  Biphasic electrical field stimulation aids in tissue engineering of multicell-type cardiac organoids. , 2011, Tissue engineering. Part A.

[81]  Van V. Brantner,et al.  Spending on new drug development1. , 2010, Health economics.

[82]  George A. Truskey,et al.  Modeling the mitochondrial cardiomyopathy of Barth syndrome with iPSC and heart-on-chip technologies , 2014, Nature Medicine.

[83]  S. Yamanaka,et al.  Induction of Pluripotent Stem Cells from Mouse Embryonic and Adult Fibroblast Cultures by Defined Factors , 2006, Cell.

[84]  George Church,et al.  Titin mutations in iPS cells define sarcomere insufficiency as a cause of dilated cardiomyopathy , 2015, Science.

[85]  D. Durrer,et al.  Total Excitation of the Isolated Human Heart , 1970, Circulation.

[86]  Milica Radisic,et al.  Oxygen gradients correlate with cell density and cell viability in engineered cardiac tissue , 2006, Biotechnology and bioengineering.

[87]  Donald M Bers,et al.  Drug Screening Using a Library of Human Induced Pluripotent Stem Cell–Derived Cardiomyocytes Reveals Disease-Specific Patterns of Cardiotoxicity , 2013, Circulation.

[88]  P. Burridge,et al.  A Review of Human Pluripotent Stem Cell-Derived Cardiomyocytes for High-Throughput Drug Discovery, Cardiotoxicity Screening, and Publication Standards , 2013, Journal of Cardiovascular Translational Research.

[89]  R. Solaro Mechanisms of the Frank-Starling law of the heart: the beat goes on. , 2007, Biophysical journal.

[90]  D. Ghista,et al.  Elastic modulus of the human intact left ventricle—determination and physiological interpretation , 1975, Medical and biological engineering.

[91]  Milica Radisic,et al.  High-density seeding of myocyte cells for cardiac tissue engineering. , 2003, Biotechnology and bioengineering.

[92]  Ofer Binah,et al.  Cardiomyocytes generated from CPVTD307H patients are arrhythmogenic in response to β-adrenergic stimulation , 2012, Journal of cellular and molecular medicine.

[93]  Pengyuan Zhang,et al.  A Fibrin Patch‐Based Enhanced Delivery of Human Embryonic Stem Cell‐Derived Vascular Cell Transplantation in a Porcine Model of Postinfarction Left Ventricular Remodeling , 2011, Stem cells.

[94]  Donald M Bers,et al.  Epigenetic Regulation of Phosphodiesterases 2A and 3A Underlies Compromised β-Adrenergic Signaling in an iPSC Model of Dilated Cardiomyopathy. , 2015, Cell stem cell.

[95]  Milica Radisic,et al.  Functional assembly of engineered myocardium by electrical stimulation of cardiac myocytes cultured on scaffolds , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[96]  Andrew M. Stuart,et al.  A First Course in Continuum Mechanics: Bibliography , 2008 .

[97]  Ying Ge,et al.  Cardiac repair in a porcine model of acute myocardial infarction with human induced pluripotent stem cell-derived cardiovascular cells. , 2014, Cell stem cell.

[98]  José Jalife,et al.  Null Mutation of Connexin 43 Causes Slow Propagation of Ventricular Activation in the Late Stages of Mouse Embryonic Development , 2001 .

[99]  James A Thomson,et al.  High purity human-induced pluripotent stem cell-derived cardiomyocytes: electrophysiological properties of action potentials and ionic currents. , 2011, American journal of physiology. Heart and circulatory physiology.

[100]  A. Katz,et al.  Ernest Henry Starling, His Predecessors, and the “Law of the Heart” , 2002, Circulation.

[101]  Thomas Boudou,et al.  A Microfabricated Platform to Measure and Manipulate the Mechanics of Engineered Cardiac Microtissues , 2012 .

[102]  Charles C Hong,et al.  Comparable calcium handling of human iPSC-derived cardiomyocytes generated by multiple laboratories. , 2015, Journal of molecular and cellular cardiology.

[103]  Thomas Eschenhagen,et al.  Engineered heart tissue for regeneration of diseased hearts. , 2004, Biomaterials.

[104]  I. Y. Chen,et al.  Reprogramming and transdifferentiation for cardiovascular development and regenerative medicine: where do we stand? , 2015, EMBO molecular medicine.

[105]  Charles E. Murry,et al.  Human Embryonic Stem Cell-Derived Cardiomyocytes Regenerate Non-Human Primate Hearts , 2014, Nature.

[106]  Bing Lim,et al.  Lessons from the heart: mirroring electrophysiological characteristics during cardiac development to in vitro differentiation of stem cell derived cardiomyocytes. , 2014, Journal of molecular and cellular cardiology.

[107]  P. Burridge,et al.  Genetic and Epigenetic Regulation of Human Cardiac Reprogramming and Differentiation in Regenerative Medicine. , 2015, Annual review of genetics.

[108]  O. Abilez,et al.  Effect of human donor cell source on differentiation and function of cardiac induced pluripotent stem cells. , 2014, Journal of the American College of Cardiology.

[109]  Sandra J. Engle,et al.  Integrating human pluripotent stem cells into drug development. , 2013, Cell stem cell.

[110]  Liang Guo,et al.  Estimating the risk of drug-induced proarrhythmia using human induced pluripotent stem cell-derived cardiomyocytes. , 2011, Toxicological sciences : an official journal of the Society of Toxicology.

[111]  C. Roy On the Influences which Modify the Work of the Heart * , 1879, The Journal of physiology.

[112]  Deborah K. Lieu,et al.  Mechanism-Based Facilitated Maturation of Human Pluripotent Stem Cell–Derived Cardiomyocytes , 2013, Circulation. Arrhythmia and electrophysiology.

[113]  Karl Deisseroth,et al.  Multiscale computational models for optogenetic control of cardiac function. , 2011, Biophysical journal.

[114]  E. Starling,et al.  The influence of variations in temperature and blood‐pressure on the performance of the isolated mammalian heart , 1912, The Journal of physiology.

[115]  S. Verheule,et al.  Cardiac electrophysiology in mice: a matter of size , 2012, Front. Physio..

[116]  N. Bursac,et al.  Functional cardiac tissue engineering. , 2012, Regenerative medicine.

[117]  Lior Gepstein,et al.  Modelling the long QT syndrome with induced pluripotent stem cells , 2011, Nature.

[118]  Kavitha T. Kuppusamy,et al.  Let-7 family of microRNA is required for maturation and adult-like metabolism in stem cell-derived cardiomyocytes , 2015, Proceedings of the National Academy of Sciences.

[119]  Nicola Elvassore,et al.  Electrical stimulation of human embryonic stem cells: cardiac differentiation and the generation of reactive oxygen species. , 2009, Experimental cell research.

[120]  Xuetao Sun,et al.  Biowire platform for maturation of human pluripotent stem cell-derived cardiomyocytes. , 2016, Methods.

[121]  Christine L Mummery,et al.  Differentiation of human embryonic stem cells and induced pluripotent stem cells to cardiomyocytes: a methods overview. , 2012, Circulation research.

[122]  W. Zimmermann,et al.  Three-dimensional engineered heart tissue from neonatal rat cardiac myocytes. , 2000, Biotechnology and bioengineering.

[123]  R. Gunnar,et al.  Improvement in symptoms and exercise tolerance by metoprolol in patients with dilated cardiomyopathy: a double-blind, randomized, placebo-controlled trial. , 1985, Circulation.

[124]  T. Ichisaka,et al.  Induction of Pluripotent Stem Cells from Adult Human Fibroblasts by Defined Factors , 2007, Cell.

[125]  H. Hecht,et al.  Electrophysiological Study of Human Heart Muscle , 1962, Circulation research.