Chris Denning a , * , Viola Borgdorff a , James Crutchley a , Karl S.A. Firth a , Vinoj George a , Spandan Kalra a , Alexander Kondrashov a , Minh Duc Hoang a , Diogo Mosqueira a , Asha Patel a , Ljupcho Prodanov a , Divya Rajamohan a , William C. Skarnes b , James G.W. Smith a , Lorraine E. Young a
1 July 2016
Human embryonic stem cells, Human induced pluripotent stem cells, Cas9/CRISPR genome editing, Cardiomyocytes, Drug screening, Disease modelling, Maturation factors, Muscular thin films, Engineered heart tissue, Automated scalability, High content platforms, Calcium imaging, Electrophysiology, Mitochondria, Contractility
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.
hPSC-CM drug screening, disease modelling & Cas9/CRISPR engineering becoming routine.
hPSC-CMs used to refine patient treatment & assist in progressing drugs to clinic.
Transplantation into heart failure pigs and primates now translated to humans.
Barriers to progression include cost of goods, subtype specification & maturation.
2D and 3D hPSC-CM high content phenotyping platforms evolving rapidly.