Dataset Information

Proteome of patient-derived iPSC-CMs with LMNA mutation

ABSTRACT: Tandem Mass Tag-Based proteomic analysis was performed to detect protein expression changes between gene correction and LMNA mutation iPSC-CMs

ORGANISM(S): Homo Sapiens

SUBMITTER: Ping Liang

PROVIDER: PXD039452 | iProX | Sun Jan 15 00:00:00 GMT 2023

REPOSITORIES: iProX

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Publications

Lamin A/C deficiency-mediated ROS elevation contributes to pathogenic phenotypes of dilated cardiomyopathy in iPSC model.

Qiu Hangyuan H Sun Yaxun Y Wang Xiaochen X Gong Tingyu T Su Jun J Shen Jiaxi J Zhou Jingjun J Xia Jiafeng J Wang Hao H Meng Xiangfu X Fu Guosheng G Zhang Donghui D Jiang Chenyang C Liang Ping P

Nature communications 20240814 1

Mutations in the nuclear envelope (NE) protein lamin A/C (encoded by LMNA), cause a severe form of dilated cardiomyopathy (DCM) with early-onset life-threatening arrhythmias. However, molecular mechanisms underlying increased arrhythmogenesis in LMNA-related DCM (LMNA-DCM) remain largely unknown. Here we show that a frameshift mutation in LMNA causes abnormal Ca<sup>2+</sup> handling, arrhythmias and disformed NE in LMNA-DCM patient-specific iPSC-derived cardiomyocytes (iPSC-CMs). Mechanisticall ...[more]

PMID: 39143095

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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.

Dataset Information

Proteome of patient-derived iPSC-CMs with LMNA mutation

Publications

Lamin A/C deficiency-mediated ROS elevation contributes to pathogenic phenotypes of dilated cardiomyopathy in iPSC model.

Similar Datasets

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