Enhancing Induced Pluripotent Stem Cell Models of Schizophrenia

Abstract

Induced pluripotent stem cell (IPSC)–based methods have become important research tools for developmental biology and molecular medicine. Reprogramming of somatic cells of either healthy or diseased individuals by the application of specific transgenes results in pluripotent and self-renewable cell lines that can be used to generate different cell types in vitro while still maintaining the genetic architecture of the donor. The prospect of IPSC models is especially tantalizing when it comes to investigating the pathophysiology of schizophrenia. Multiple lines of evidence support the neurodevelopmental hypothesis of schizophrenia, which postulates that early developmental brain alterations lead to increased vulnerability for schizophrenia in adolescence and early adulthood. Until recently, investigation of the developmental origins of schizophrenia using human neurons has been all but impossible. However, with the discovery of IPSC models, it is now plausible that such faulty neurodevelopment could be recapitulated in vitro through neural progenitor cells (NPCs) and their differentiation to neurons. Compared with the relatively straightforward nature of modeling disorders with known monogenic etiology, schizophrenia presents a far more daunting prospect. The list of genes implicated in the disorder stretches into the hundreds, in addition to a myriad of environmental factors believed to contribute to disease risk. Consequently, one of the major challenges facing IPSC models of schizophrenia is identifying common mechanisms or phenotypes linked to the disease. To date, all IPSC studies attempting to model schizophrenia have done so using cells generated from a handful of patients. Such studies have already revealed promising insights into developmental abnormalities within the neurons of patients, such as deficiencies in neural connectivity and neurite outgrowth, along with the misexpression of several genes previously implicated in schizophrenia, including NRG1, ZNF804A, and TCF4. 1 Yet, given the low number of cell lines investigated and the studies’ methodological heterogeneity, it is questionable how generalizable these findings are and to what extent they can provide relevant insights into disease pathology in vivo. Ideally, one could envision comparing hundreds of IPSC lines in order to identify common phenotypic deficiencies linked to schizophrenia, in much the same way that large-scale genetic studies recruit thousands of patients in the hunt for new disease-related mutations. However, given the extensive amount of time and resources required to generate and test IPSC lines, such small-scale studies are likely to be the norm for the foreseeable future. How then can future IPSC models of schizophrenia be enhanced to reduce variability between studies and improve the chances of identifying clinically relevant phenotypes?