Human stem cells and surrogate tissues for basic and translational study of mental disorders

摘要

The mechanisms underlying the complex, multifactorial nature of psychiatric disorders has eluded researchers for decades (1). Although there are rare familial cases that appear to involve defined, highly penetrant genetic mutations, most cases are sporadic and polygenic. To complicate the etiology further, environmental interactions with the genotype appear to influence the phenotype. The polygenic basis of psychiatric conditions limits the usefulness of genetic mouse models, which are often used to model known mutations. Although the recently introduced clustered regularly interspaced short palindromic repeat (CRISPR) system may allow efficient mutation of genes at multiple sites (2), it still depends on a prior understanding of specific mutations involved. In contrast, human cells and biospecimens may offer advantages over animal models in studying the biology underlying psychiatric conditions at the molecular level, because they are likely to reflect patient-derived genetic architectures. Several types of human biospecimens can be used for research, including 1) postmortem brains; 2) surrogate tissues obtained from a biopsy, such as blood, cerebrospinal fluid, and olfactory tissues; and 3) recently developed genetically engineered cells, which include induced pluripotent stem (iPS) cells, induced neuronal (iN) cells, and induced neural progenitor cells. These different types of samples can complement each other, and the advantages and limitations of each are described (Table 1).