Unknown,Transcriptomics,Genomics,Proteomics

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Donor-to-donor variation in gene expression profile of 3D bronchial epithelial cells after cigarette smoke exposure

ABSTRACT: Three-dimensional (3D) cultured primary cells are used to predict the toxicity of substances towards humans because these 3D cultures closely mimic the physiological architecture of tissues. Nonetheless, it is important to consider primary-cell-specific variability for endpoint selection and appropriate evaluation of toxicity because donor-dependent characteristics may be retained even in in vitro cell cultures. In this experiment, 3D differentiated bronchial epithelial cells from three donors were used to investigate donor-to-donor variability, with an aqueous extract of cigarette smoke used as the test substance. Therefore, global gene expression analysis was performed to expand and deepen our insight into the variability.

ORGANISM(S): Homo sapiens

SUBMITTER: Sakura Mori

PROVIDER: E-MTAB-11316 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Many oncology drugs have been found to induce cardiotoxicity in a subset of patients, which significantly limits their clinical use and impedes the benefit of lifesaving anti-cancer treatments. Human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) carry donor-specific genetic information and have been proposed for explore the inter-individual difference in oncology drug-induced cardiotoxicity. Herein, we evaluated the inter- and intra- individual variability of iPSC-CM-related assays and presented a practical approach for using donor-specific iPSC-CMs to predict personalized doxorubicin (DOX)-induced cardiotoxicity (DIC) prior to chemotherapy. Our findings demonstrated that donor-specific iPSC-CMs exhibited greater line-to-line variability than the intra-individual variability in impedance cytotoxicity and transcriptome assays. The variable and dose-dependent cytotoxic responses of iPSC-CMs resembled those observed in clinical practice, and largely replicated the reported mechanisms of DIC. By categorizing iPSC-CMs into DOX-resistant and DOX-sensitive cell lines based on their phenotypic reactions to DOX, we found that the sensitivity of donor-specific iPSC-CMs to DOX may predict in vivo DIC risk. Furthermore, we assessed the limitations of the model for identification of potential genetic/molecular biomarker and pinpointed a differentially expressed gene, DND microRNA-mediated repression inhibitor 1 (DND1), between the DOX-resistant and DOX-sensitive iPSC-CMs. We also discussed the selection of DOX dose and exposure duration for inter-individual variability of DIC assessment. Our results support the utility of donor-specific iPSC-CMs in assessing inter-individual difference and enabling personalized cardiotoxicity prediction. Further studies will encompass a large panel of donor-specific iPSC-CMs to investigate the role of the DND1 and known DIC genetic variants, and to identify potential novel molecular and genetic biomarkers for predicting DOX and other oncology drug-induced cardiotoxicity.

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Donor-to-donor variation in gene expression profile of 3D bronchial epithelial cells after cigarette smoke exposure

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