Human iPSC models provide an invaluable tool to dissect the molecular and pathophysiological defects underlying neuropsychiatric disorders and offer a powerful platform for drug screening in disease-relevant cells. Although this system addresses many challenges associated with studying mental illness, important limitations remain.89 First, epigenetic erasure: the current dogma in the field states that upon reprogramming, not only is the cellular lineage identity reset, but the epigenetic landscape of the cell is erased.90 This gives the cell a relatively clean slate on which to form the modifications necessary to differentiate into any cell type of the body, much like the germline reprogramming that facilitates totipotency in the mammalian zygote.91 However, this is problematic for the study of neuropsychiatric diseases, such as depression or anxiety, which are greatly influenced by environmental factors known to modify epigenetics. There is evidence that some epigenetic memory is retained through the reprogramming process, which is supported by the tendency of iPSCs derived from blood cells to preferentially differentiate toward mesoderm lineages (that is, their lineage of origin).28 However, such epigenetic memory may not persist long-term in
