Implications and limitations of cellular reprogramming for psychiatric drug development

Abstract

Human-induced pluripotent stem cells (hiPSCs) derived from somatic cells of patients have opened possibilities for in vitro modeling of the physiology of neural (and other) cells in psychiatric disease states. Issues in early stages of technology development include (1) establishing a library of cells from adequately phenotyped patients, (2) streamlining laborious, costly hiPSC derivation and characterization, (3) assessing whether mutations or other alterations introduced by reprogramming confound interpretation, (4) developing efficient differentiation strategies to relevant cell types, (5) identifying discernible cellular phenotypes meaningful for cyclic, stress induced or relapsing–remitting diseases, (6) converting phenotypes to screening assays suitable for genome-wide mechanistic studies or large collection compound testing and (7) controlling for variability in relation to disease specificity amidst low sample numbers. Coordination of material for reprogramming from patients well-characterized clinically, genetically and with neuroimaging are beginning, and initial studies have begun to identify cellular phenotypes. Finally, several psychiatric drugs have been found to alter reprogramming efficiency in vitro, suggesting further complexity in applying hiPSCs to psychiatric diseases or that some drugs influence neural differentiation moreso than generally recognized. Despite these challenges, studies utilizing hiPSCs may eventually serve to fill essential niches in the translational pipeline for the discovery of new therapeutics.

Induced Pluripotent Stem Cells as a Novel Tool in Psychiatric Research

“…Second, amelioration of the altered phenotypes of patient's hiPSCs using new classes of drugs that demonstrate therapeutic efficacy towards known or novel targets enable researchers to establish valuable drug screening and drug discovery tools. Most of the studies at present actually belong to the former category, since the latter faces limitations, 61 which could be overcome in the near future by technological advances (mentioned later).…”

The Application and Future of Neural Stem Cells in Regenerative Medicine

“…And it is unknown to what extent patient exposure to psychiatric medications, several of which have been independently found to influence in vitro dedifferentiation, will confound PSC studies derived from those patients [41]. Small patient samplings from practical limitations of PSC generation, characterization and differentiation engender the risk of amplifying or overemphasizing artifacts or stochastic differences between patient cell samples including those resulting from acquired mutations.…”

The Future of Neuroepigenetics in the Human Brain

“…Given the considerable variability of epigenetic and cellular phenotypes after reprogramming, 156,157 it will be difficult to faithfully “rebuild” in the culture dish the cortical neuronal networks with their constituents such as pyramidal neurons and their surrounding inhibitory cells. This is a challenge for any disease-related study, including many psychiatric disorders that are likely to show only subtle differences in cellular response patterns, as compared with controls.…”