One of the major advantages of the iPSC technology for modeling human diseases is that iPSCs contain the entire genetic background of the donor, making the technology particularly suitable to study diseases caused by defined genetic errors. One downside, however, is that epigenetic memory is erased during the reprogramming process. This poses a challenge to the study neuropsychiatric disorders which are greatly influenced by environmental factors known to leave their mark via epigenetic modifications. A sister technology to the traditional iPSC reprogramming method, called transdifferentiation (or direct reprogramming), circumvents the issue of epigenetic erasure by using transcription factors to directly induce a somatic cell to switch fates without passing through the pluripotent stem cell intermediate.27 This has been used to generate functional-induced neurons (iNs) directly from fibroblasts.27 Of note, transdifferentiated cells appear to retain much of their original epigenetic landscape28(discussed in more detail in Limitations and Moving Forward in this review). Thus, generating iNs could be a valid alternative for the modeling of environmentally induced neuropsychiatric diseases, assuming that the epigenetic changes present in the somatic cells of the patient, such as in skin fibroblasts, are relevant in the context of modeling a neuropsychiatric disease.
