New lessons learned from disease modeling with induced pluripotent stem cells

Abstract

Cellular reprogramming and generation of induced pluripotent stem cells (iPSCs) from adult cell types have enabled the creation of patient-specific stem cells for use in disease modeling. To date, many iPSC lines have been generated from a variety of disorders, which have then been differentiated into disease-relevant cell types. When a disease-specific phenotype is detectable in such differentiated cells, the reprogramming technology provides a new opportunity to identify aberrant disease-associated pathways and drugs that can block them. Here, we highlight recent progress as well as limitations in the use of iPSCs to recapitulate disease phenotypes and to screen for therapeutics in vitro.

Figure 1. Disease modeling and drug discovery using patient-derived iPSCs

Generation of an iPSC-based disease model starts with cells isolated from patients, usually by a skin punch biopsy. Upon reprogramming, several iPSC clones are selected, expanded and characterized. High-quality iPSCs are then differentiated into mature cell types exhibiting a disease-specific phenotype that is readily detected by cellular and/or molecular assays. High-throughput screens based on such assays can be carried out to discover therapeutics that reverse the disease phenotypes. Hits from these screens are candidates for lead optimization by medicinal chemistry, and then further preclinical studies.