Current status of drug screening and disease modelling in human pluripotent stem cells

Abstract

The emphasis in human pluripotent stem cell (hPSC) technologies has shifted from cell therapy to in vitro disease modelling and drug screening. This review examines why this shift has occurred, and how current technological limitations might be overcome to fully realise the potential of hPSCs. Details are provided for all disease-specific human induced pluripotent stem cell lines spanning a dozen dysfunctional organ systems. Phenotype and pharmacology have been examined in only 17 of 63 lines, primarily those that model neurological and cardiac conditions. Drug screening is most advanced in hPSC-cardiomyocytes. Responses for almost 60 agents include examples of how careful tests in hPSC-cardiomyocytes have improved on existing in vitro assays, and how these cells have been integrated into high throughput imaging and electrophysiology industrial platforms. Such successes will provide an incentive to overcome bottlenecks in hPSC technology such as improving cell maturity and industrial scalability whilst reducing cost.

Figure 1

Current status and emerging technologies in disease modelling and drug screening for hiPSC-based models of human genetic disease. hiPCS-based models of human disease affecting the heart, smooth muscle, skeletal muscle, skin, central nervous system (CNS), liver, blood and eye have been generated. However, only those affecting the heart, CNS and eye have been used to evaluate the effects of drug treatment. Emerging technologies for scale-up, automation and high throughput analysis will enable use of hiPSC-disease models for drug discovery and safety evaluation in an industrial setting. Green and blue arrows show processes amenable to scale-up and automation, or high-content imaging and electrophysiology analysis.