期刊
CELL STEM CELL
卷 19, 期 3, 页码 311-325出版社
CELL PRESS
DOI: 10.1016/j.stem.2016.07.006
关键词
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资金
- NIH [R01 HL113006, R01 HL123968, R01 HL130020, R01 HL126527, R01 HL128170, P01 GM099130, K99 HL121177, K99 HL104002]
- Burroughs Wellcome Foundation Innovation in Regulatory Science Award
- California Institute for Regenerative Medicine Center of Excellence for Stem Cell Genomics grant [GC1R-06673-A]
- National Heart, Lung, and Blood Institute Progenitor Cell Biology Jump Start Award
- American Heart Association (AHA) [16BGIA27790017]
- Stanford Cardiovascular Institute Seed Grant
- AHA [14BGIA20480329, 15BGIA22730027]
- Winston Chen Stanford Graduate Fellowship
- Stanford CVI Seed Grant
Understanding individual susceptibility to drug-induced cardiotoxicity is key to improving patient safety and preventing drug attrition. Human induced pluripotent stem cells (hiPSCs) enable the study of pharmacological and toxicological responses in patient-specific cardiomyocytes (CMs) and may serve as preclinical platforms for precision medicine. Transcriptome profiling in hiPSC-CMs from seven individuals lacking known cardiovascular disease-associated mutations and in three isogenic human heart tissue and hiPSC-CM pairs showed greater interpatient variation than intra-patient variation, verifying that reprogramming and differentiation preserve patient-specific gene expression, particularly in metabolic and stress-response genes. Transcriptomebasedtoxicology analysis predicted and risk-stratified patient-specific susceptibility to cardiotoxicity, and functional assays in hiPSC-CMs using tacrolimus androsiglitazone, drugs targeting pathways predicted to produce cardiotoxicity, validated inter-patient differential responses. CRISPR/Cas9-mediated pathway correction prevented drug-induced cardiotoxicity. Our data suggest that hiPSC-CMs can be used in vitro to predict and validate patient-specific drug safety and efficacy, potentially enabling future clinical approaches to precision medicine.
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