Implications and limitations of cellular reprogramming for psychiatric drug development
Open Access
- 15 November 2013
- journal article
- review article
- Published by Springer Science and Business Media LLC in Experimental & Molecular Medicine
- Vol. 45 (11), e59
- https://doi.org/10.1038/emm.2013.124
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.Keywords
This publication has 106 references indexed in Scilit:
- Modeling complex neuropsychiatric disorders with human induced pluripotent stem cellsCurrent Opinion in Pharmacology, 2011
- Lithium, an anti-psychotic drug, greatly enhances the generation of induced pluripotent stem cellsCell Research, 2011
- Embryonic stem cell-derived motoneurons provide a highly sensitive cell culture model for botulinum neurotoxin studies, with implications for high-throughput drug discoveryStem Cell Research, 2011
- LRRK2 Mutant iPSC-Derived DA Neurons Demonstrate Increased Susceptibility to Oxidative StressCell Stem Cell, 2011
- Integration-free induced pluripotent stem cells derived from schizophrenia patients with a DISC1 mutationMolecular Psychiatry, 2011
- A Model for Neural Development and Treatment of Rett Syndrome Using Human Induced Pluripotent Stem CellsCell, 2010
- Histone acetylation in drug addictionSeminars in Cell & Developmental Biology, 2009
- Differential Allelic Expression of Dopamine D1 Receptor Gene (DRD1) Is Modulated by microRNA miR-504Biological Psychiatry, 2009
- Neural differentiation of human embryonic stem cellsJournal of Cellular Biochemistry, 2008
- Histone H3 Lysine 4 Demethylation Is a Target of Nonselective Antidepressive MedicationsCell Chemical Biology, 2006