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.
Highlights
PHARMACOLOGIC USE AND DISCOVERY IN NEUROPSYCHIATRIC DISORDERS Optimal pharmacologic management of multifactorial disorders depends upon understanding interactions with diverse and complex mechanistic drug targets, subcategorizing patients based on the most informative and drug-responsive phenotypes, and producing the maximal likelihood of therapeutic responses through utilization of complementary classes of pharmacologic agents
The authors of this study identified baseline differences in neural differentiation between patients unaffected and with schizophrenia
We have found that expression of circadian genes can be used to trace rhythms in Human-induced pluripotent stem cells (hiPSCs)-derived neural cells (Tobe BT, Brandel MG, McCarthy M and Snyder EY, unpublished data)
Summary
PHARMACOLOGIC USE AND DISCOVERY IN NEUROPSYCHIATRIC DISORDERS Optimal pharmacologic management of multifactorial disorders depends upon understanding interactions with diverse and complex mechanistic drug targets, subcategorizing patients based on the most informative and drug-responsive phenotypes, and producing the maximal likelihood of therapeutic responses through utilization of complementary classes of pharmacologic agents. ‘Pluripotency’ was initially described in embryonic stem cells (ESCs) derived from mammalian blastocysts which, when cultured, can self-renew and differentiate in vitro into the three primordial germ layers (barring extraembryonic tissues), mesoderm, ectoderm and endoderm.[27] despite development of differentiation strategies for human ESCs to divergent cell types and the fact that diseased blastocysts could occasionally be obtained from in vitro fertility clinics based on prenatal genetic diagnosis, they were not ideally suited for disease modeling because of the ethical challenges of obtaining them, limited availability and, in normal human ESCs, poor amenability to genetic engineering for simulating disease-related mutations This obstacle was overcome by development of fate reprogramming through the expression of specific combinations of exogenous factors, c-Myc, Klf[4], Oct3/4, Sox[2], Nanog, Lin[28], in somatic cell types
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