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Trends Mol Med. 2018 Sep;24(9):805-820. doi: 10.1016/j.molmed.2018.06.009. Epub 2018 Jul 11.

Pluripotent Stem Cell Platforms for Drug Discovery.

Author information

1
NIH Stem Cell Characterization Facility, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: cheng@mail.nih.gov.
2
NIH Stem Cell Characterization Facility, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
3
Skeletal Biology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA.
4
The Lieber Institute for Brain Development, Baltimore, MD 21205, USA.
5
The Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
6
National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA.

Abstract

Use of human pluripotent stem cells (hPSCs) and their differentiated derivatives have led to recent proof-of-principle drug discoveries, defining a pathway to the implementation of hPSC-based drug discovery (hPDD). Current hPDD strategies, however, have inevitable conceptual biases and technological limitations, including the dimensionality of cell-culture methods, cell maturity and functionality, experimental variability, and data reproducibility. In this review, we dissect representative hPDD systems via analysis of hPSC-based 2D-monolayers, 3D culture, and organoids. We discuss mechanisms of drug discovery and drug repurposing, and roles of membrane drug transporters in tissue maturation and hPDD using the example of drugs that target various mutations of CFTR, the cystic fibrosis transmembrane conductance regulator gene, in patients with cystic fibrosis.

KEYWORDS:

ATP-binding cassette; CFTR; Pluripotent stem cells; cystic fibrosis; differentiation; drug discovery; organoids

PMID:
30006147
PMCID:
PMC6117164
[Available on 2019-09-01]
DOI:
10.1016/j.molmed.2018.06.009
[Indexed for MEDLINE]

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