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The human amniotic fluid stem cell secretome counteracts doxorubicin-induced cardiotoxicity

ABSTRACT: The anthracycline, doxorubicin (Dox), is widely used in oncology, but it may it may cause a cardiomyopathy which has dismal prognosis and cannot be effectively prevented. The secretome of multipotent human amniotic fluid-derived stem cells (hAFS) has previously been demonstrated to reduce ischemic cardiac damage. Here, it is shown that the hAFS conditioned medium (hAFS-CM) antagonizes senescence and apoptosis of cardiomyocytes and cardiac progenitor cells, two major features of Dox cardiotoxicity. Mechanistic studies with primary mouse neonatal cardiomyocytes reveal that hAFS-CM inhibition of Dox-elicited senescence and apoptosis is paralleled by decreased DNA damage and is associated with nuclear translocation of NF-kB and upregulation of a set of genes controlled by NF-kB, namely Il6 and Cxcl1, which promote cardiomyocyte survival, and Cyp1b1 and Abcb1, which encode for proteins involved in Dox metabolism and efflux, respectively. The PI3K/Akt signaling cascade, upstream of NF-kB, is potently activated by the hAFS-CM and pre-treatment with a PI3K inhibitor abrogates NF-kB accumulation into the nucleus, modulation of its target genes, and prevention of Dox-initiated senescence and apoptosis in response to the hAFS-CM. This work may lay the ground for the development of a stem cell-based paracrine therapy of chemotherapy-related cardiotoxicity.

ORGANISM(S): Mus musculus

PROVIDER: GSE74513 | GEO | 2016/10/30

SECONDARY ACCESSION(S): PRJNA300621

REPOSITORIES: GEO

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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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The human amniotic fluid stem cell secretome counteracts doxorubicin-induced cardiotoxicity

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