Fig. 12

1 The process of deriving and utilizing human induced pluripotent stem (iPS) cells. It shows that adult somatic cells, which are specialized cells in the body, can be reprogrammed into iPS cells capable of differentiating into various cell types. These iPS cells have several applications. a) One application is disease modeling, where human iPS cells are used to investigate the molecular mechanisms behind disease phenotypes. For example, they can be employed to study the molecular causes of arrhythmia in cardiomyocytes or defects in neurogenic differentiation. b) Human iPS cells can also be utilized in drug screening and discovery. They help determine the effects of candidate drugs and new compounds and identify target pathways. c) Another valuable application of human iPS cells is in conducting toxicity tests for cardiac, neural, and liver cells. These tests assess the toxic responses of cells to drugs and substances. Combining drug screening and toxicity tests allows for human preclinical trials in a controlled laboratory setting, enabling early involvement of “the patient” in the drug discovery process. 2 The use of human induced pluripotent stem (iPS) cells for modeling cardiac and neural diseases and the improvement of disease symptoms. In the first scenario (a), skin fibroblasts taken from a patient with type 1 long QT syndrome (LQT1), which is caused by a mutation in the KCNQ1 potassium channel gene, were reprogrammed into iPS cells using retroviral transduction of four specific genes. These iPS cells were then transformed into clusters called embryoid bodies and subsequently differentiated into cardiomyocytes. The presence of spontaneous contraction in these cells indicated the existence of functioning heart muscle cells. By applying isoprenaline, a substance that mimics β-adrenergic stress, arrhythmic events similar to those observed in LQT1 patients' hearts were induced in the cardiomyocytes. However, when the β-blocker propranolol was administered, the arrhythmia was suppressed. In the second scenario (b), skin fibroblasts were obtained from a patient with Rett syndrome (RTT), which is caused by a mutation in the MECP2 gene responsible for regulating epigenetic processes. These fibroblasts were reprogrammed into human iPS cells using retroviral transduction of the same four genes mentioned earlier. The iPS cells were then differentiated into embryoid bodies, and the appearance of rosette structures indicated the presence of neural precursors. Further differentiation of these precursors resulted in the formation of glutamatergic neurons. These neurons exhibited reduced numbers of glutamatergic synapses (represented by red dots) and a decrease in soma size (the cell body of the neuron). However, treatment with insulin-like growth factor 1 (IGF1) caused an increase in both the number of glutamatergic synapses and the size of the neuron's soma. Reprinted from [726] with permission from the Springer Nature