title: Cardiomyocytes from human pluripotent stem cells: From laboratory curiosity to industrial biomedical platform.
abstract: Cardiomyocytes from human pluripotent stem cells (hPSCs-CMs) could revolutionise biomedicine. Global burden of heart failure will soon reach USD $90bn, while unexpected cardiotoxicity underlies 28% of drug withdrawals. Advances in hPSC isolation, Cas9/CRISPR genome engineering and hPSC-CM differentiation have improved patient care, progressed drugs to clinic and opened a new era in safety pharmacology. Nevertheless, predictive cardiotoxicity using hPSC-CMs contrasts from failure to almost total success. Since this likely relates to cell immaturity, efforts are underway to use biochemical and biophysical cues to improve many of the ~30 structural and functional properties of hPSC-CMs towards those seen in adult CMs. Other developments needed for widespread hPSC-CM utility include subtype specification, cost reduction of large scale differentiation and elimination of the phenotyping bottleneck. This review will consider these factors in the evolution of hPSC-CM technologies, as well as their integration into high content industrial platforms that assess structure, mitochondrial function, electrophysiology, calcium transients and contractility. This article is part of a Special Issue entitled: Cardiomyocyte Biology: Integration of Developmental and Environmental Cues in the Heart edited by Marcus Schaub and Hughes Abriel.
authors.affiliation: Department of Stem Cell Biology, Centre for Biomolecular Sciences, University of Nottingham, NG7 2RD, United Kingdom. Electronic address: chris.denning@nottingham.ac.uk.
authors.forename: Chris
authors.initials: C
authors.lastname: Denning
authors.affiliation: Department of Stem Cell Biology, Centre for Biomolecular Sciences, University of Nottingham, NG7 2RD, United Kingdom.
authors.forename: Viola
authors.initials: V
authors.lastname: Borgdorff
authors.affiliation: Department of Stem Cell Biology, Centre for Biomolecular Sciences, University of Nottingham, NG7 2RD, United Kingdom.
authors.forename: James
authors.initials: J
authors.lastname: Crutchley
authors.affiliation: Department of Stem Cell Biology, Centre for Biomolecular Sciences, University of Nottingham, NG7 2RD, United Kingdom.
authors.forename: Karl S A
authors.initials: KS
authors.lastname: Firth
authors.affiliation: Department of Stem Cell Biology, Centre for Biomolecular Sciences, University of Nottingham, NG7 2RD, United Kingdom.
authors.forename: Vinoj
authors.initials: V
authors.lastname: George
authors.affiliation: Department of Stem Cell Biology, Centre for Biomolecular Sciences, University of Nottingham, NG7 2RD, United Kingdom.
authors.forename: Spandan
authors.initials: S
authors.lastname: Kalra
authors.affiliation: Department of Stem Cell Biology, Centre for Biomolecular Sciences, University of Nottingham, NG7 2RD, United Kingdom.
authors.forename: Alexander
authors.initials: A
authors.lastname: Kondrashov
authors.affiliation: Department of Stem Cell Biology, Centre for Biomolecular Sciences, University of Nottingham, NG7 2RD, United Kingdom.
authors.forename: Minh Duc
authors.initials: MD
authors.lastname: Hoang
authors.affiliation: Department of Stem Cell Biology, Centre for Biomolecular Sciences, University of Nottingham, NG7 2RD, United Kingdom.
authors.forename: Diogo
authors.initials: D
authors.lastname: Mosqueira
authors.affiliation: Department of Stem Cell Biology, Centre for Biomolecular Sciences, University of Nottingham, NG7 2RD, United Kingdom.
authors.forename: Asha
authors.initials: A
authors.lastname: Patel
authors.affiliation: Department of Stem Cell Biology, Centre for Biomolecular Sciences, University of Nottingham, NG7 2RD, United Kingdom.
authors.forename: Ljupcho
authors.initials: L
authors.lastname: Prodanov
authors.affiliation: Department of Stem Cell Biology, Centre for Biomolecular Sciences, University of Nottingham, NG7 2RD, United Kingdom.
authors.forename: Divya
authors.initials: D
authors.lastname: Rajamohan
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom.
authors.forename: William C
authors.initials: WC
authors.lastname: Skarnes
authors.affiliation: Department of Stem Cell Biology, Centre for Biomolecular Sciences, University of Nottingham, NG7 2RD, United Kingdom.
authors.forename: James G W
authors.initials: JG
authors.lastname: Smith
authors.affiliation: Department of Stem Cell Biology, Centre for Biomolecular Sciences, University of Nottingham, NG7 2RD, United Kingdom.
authors.forename: Lorraine E
authors.initials: LE
authors.lastname: Young
mesh_terms: D035843:Biomedical Research / Q000379:methods*; D002317:Cardiovascular Agents / Q000494:pharmacology* / Q000633:toxicity; D002454:Cell Differentiation; D019070:Cell Lineage; D049109:Cell Proliferation; D002478:Cells, Cultured; D055808:Drug Discovery / Q000379:methods*; D005838:Genotype; D006331:Heart Diseases / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D057166:High-Throughput Screening Assays; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D010641:Phenotype; D018570:Risk Assessment; D018675:Toxicity Tests / Q000379:methods*
chemical_list: D002317:Cardiovascular Agents
keywords: Automated scalability; Calcium imaging; Cardiomyocytes; Cas9/CRISPR genome editing; Contractility; Disease modelling; Drug screening; Electrophysiology; Engineered heart tissue; High content platforms; Human embryonic stem cells; Human induced pluripotent stem cells; Maturation factors; Mitochondria; Muscular thin films