Human pluripotent-stem-cell-derived organoids for drug discovery and evaluation

Human pluripotent stem cells (hPSCs) and three-dimensional organoids have ushered in a new era for disease modeling and drug discovery. Over the past decade, significant progress has been in deriving functional organoids from hPSCs, which have been applied to recapitulate disease phenotypes. In addition, these advancements have extended the application of hPSCs and organoids for drug screening and clinical-trial safety evaluations. This review provides an overview of the achievements and challenges in using hPSC-derived organoids to conduct relevant high-throughput, high-contentscreens and drug evaluation. These studies have greatly enhanced our knowledge and toolbox for precision medicine.

Human pluripotent stem cells (hPSCs), which include human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs), are defined by their ability to both self-renew and differentiate into almost all terminally differentiated cells in the human body. hESCs were first derived in 1998 from the inner cell mass of pre-implantation embryos.1 In 2006, mouse fibroblasts were reprogrammed into pluripotent cells known as iPSCs.2 Similarly, human iPSCs (hiPSCs) were derived shortly after.2,3

Since their discovery, there have been significant efforts to apply hPSCs for disease modeling and drug discovery. iPSCs were derived from diseased patients and healthy individuals to model the cellular phenotypes involved in disease progression. Isogenic hPSCs were used for studying the impact of a single gene, regulatory region, or genetic variants (single-nucleotide polymorphisms [SNPs)) on cell fate4 (Figure 1). These models have served extensively as drug-discovery platforms and predictive indicators of drug response, leading to the development of unique therapeutic candidates and paving the way for the development of precision medicine.