Induced pluripotent stem cells as a disease modeling and drug screening platform

Abstract

Induced pluripotent stem cells (iPSCs) hold great hopes for therapeutic application in various diseases. Although ongoing research is dedicated to achieving clinical translation of iPSCs, further understanding of the mechanisms that underlie complex pathogenic conditions is required. Compared with other classical models for studying diseases, iPSCs provide considerable advantages. A newly emerging application of iPSCs is in vitro disease modeling, which can significantly improve the never-ending search for new pharmacological cures. Here, we will discuss current efforts to create iPSC-dependent patient-specific disease models. Furthermore, we will review the use of iPSCs for development and testing of new therapeutic agents and the implications for high-throughput drug screening.

Figure 1. Application of iPSCs for regenerative medicine, disease modeling, and drug screening

After reprogramming of somatic, patient-derived cells to an induced pluripotent state, iPSCs can be differentiated into cell types of all three germ layers, allowing regeneration of tissue and posing great hopes for clinical translation of iPSCs and treatment of many diseases. Also, iPSC-derived tissue-specific cells may be employed for modeling diseases to understand the complex mechanisms underlying various diseases, and for assessing cytotoxicity of small chemicals in drug development. This illustrates how iPSCs provide an improved model system for disease modeling, high-throughput drug screening, and toxicity testing.

Figure 2. Schematic representation of cardiac drug screening and toxicity testing with human iPSC technology

Cardiomyocytes are differentiated from normal or disease-specific, patient-derived iPSCs. Subsequently, these iPSC-derived cardiomyocytes (iPSC-CMs) undergo drug screening and toxicity testing with existing or novel drugs. The baseline properties of iPSC-CMs and their response to drugs are determined by electrophysiological assays such as extracellular multi-electrode array (MEA) and patch clamp recordings, using beating embryonic bodies (EBs) in MEA experiments (MED64 MEA amplifier, Alpha Med Scientific, Japan) and isolated single cardiomyocytes in patch clamp recordings (EPC-10 patch clamp amplifier, HEKA, Germany), respectively. Here, nifedipine (100nM) is tested in iPSC-CMs, which showed a significant shortening of field potential duration (FPD) on MEA compared to baseline. Similarly, nifedipine is tested with patch clamp recordings in a dose-dependent manner and exhibited an effect consistent with MEA data.