Expression-based drug screening of neural progenitor cells from individuals with schizophrenia.
Benjamin ReadheadBrigham J HartleyBrian J EastwoodDavid A CollierDavid EvansRichard FariasChing HeGabriel E HoffmanPamela SklarJoel T DudleyEric E SchadtRadoslav SavićKristen J BrennandPublished in: Nature communications (2018)
A lack of biologically relevant screening models hinders the discovery of better treatments for schizophrenia (SZ) and other neuropsychiatric disorders. Here we compare the transcriptional responses of 8 commonly used cancer cell lines (CCLs) directly with that of human induced pluripotent stem cell (hiPSC)-derived neural progenitor cells (NPCs) from 12 individuals with SZ and 12 controls across 135 drugs, generating 4320 unique drug-response transcriptional signatures. We identify those drugs that reverse post-mortem SZ-associated transcriptomic signatures, several of which also differentially regulate neuropsychiatric disease-associated genes in a cell type (hiPSC NPC vs. CCL) and/or a diagnosis (SZ vs. control)-dependent manner. Overall, we describe a proof-of-concept application of transcriptomic drug screening to hiPSC-based models, demonstrating that the drug-induced gene expression differences observed with patient-derived hiPSC NPCs are enriched for SZ biology, thereby revealing a major advantage of incorporating cell type and patient-specific platforms in drug discovery.
Keyphrases
- drug induced
- liver injury
- gene expression
- drug discovery
- stem cells
- adverse drug
- genome wide
- bipolar disorder
- endothelial cells
- dna methylation
- single cell
- transcription factor
- poor prognosis
- small molecule
- high glucose
- squamous cell carcinoma
- papillary thyroid
- high throughput
- emergency department
- induced pluripotent stem cells
- bone marrow
- binding protein
- squamous cell
- oxidative stress
- diabetic rats
- pluripotent stem cells