Drug Discovery Models and Toxicity Testing Using Embryonic and Induced Pluripotent Stem-Cell-Derived Cardiac and Neuronal Cells

Abstract

Development of induced pluripotent stem cells (iPSCs) using forced expression of specific sets of transcription factors has changed the field of stem cell research extensively. Two important limitations for research application of embryonic stem cells (ESCs), namely, ethical and immunological issues, can be circumvented using iPSCs. Since the development of first iPSCs, tremendous effort has been directed to the development of methods to increase the efficiency of the process and to reduce the extent of genomic modifications associated with the reprogramming procedure. The established lineage-specific differentiation protocols developed for ESCs are being applied to iPSCs, as they have great potential in regenerative medicine for cell therapy, disease modeling either for drug development or for fundamental science, and, last but not least, toxicity testing. This paper reviews efforts aimed at practical development of iPSC differentiation to neural/cardiac lineages and further the use of these iPSCs-derived cells for drug development and toxicity testing.

Establishment of a translational endothelial cell model using directed differentiation of induced pluripotent stem cells from Cynomolgus monkey

“…Thus, IPSC technology is increasingly being explored to analyze and predict adverse drug reactions in the liver, heart or neurons. While such systems have been successfully developed for humans222324 and are the focus of intensive validation25, similar models for NHPs are still lacking. However, due to the increasing complexity and species-specificity of novel drugs, such as therapeutic antibodies or RNA therapeutics (e.g., ASOs, siRNA), there is an increasing need to use NHPs for in vivo studies, which implies an increased need for predictive NHP in vitro systems.…”

Mesenchymal Stem Cells: An Innovative Approach in Pharmacokinetics

“…It is demonstrated that iPSCs are currently being used for high-throughput screening and chronic toxicity assessment of cardiac, hepatic, and nervous tissues [29]. Recent report by Deshmukh et al [30] describes that ES cells and iPSCs are efficiently used to screen cardiac and neurotoxic agents. iPSCs derived from different somatic cells may be used to produce unrepaired somatic cells for disease modeling or drug screening (Fig.…”

Guidelines for Preclinical Development

“…In an early study of a human neural stem cell line derived from umbilical cord blood, several stages of neural commitment and differentiation were established and less differentiated cells were shown to be more sensitive to neurotoxins (Buzanska et al 2009 ). Changes in intracellular calcium may also provide a useful indication of neurotoxicity, offering an alternative to PC12 cells and other immortalized cell lines that display a partial neuronal phenotype and/or are derived from non-human species (Deshmukh et al 2012 ). With these encouraging developments, the next challenge is to standardize protocols for neurotoxicology testing with iPSC derived progenitors and differentiated cells.…”