Use single cell RNA-seq to investigate human pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) exposed to the cardiotoxic drug doxorubicin. Expected research outcome is to identify subpopulations of cell types within the differentiated cardiomyocytes, and to investigate differences in the toxic response between these subpopulations.
Doxorubicin is an anthracycline that is used as chemotherapy for some cancer patients. Drug-induced cardiotoxicity from doxorubicin therapy affects a subpopulation of the treated patients, and possibilities to predict the propensity for a patient to suffer from this severe side effect would be of great value when deciding appropriate chemotherapy intervention. Interestingly, a recent study by Burridge et al. demonstrated the utility of patient specific hiPSC-derived cardiomyocytes to assess the risk of doxorubicin-induced cardiotoxicity at the cellular level. The authors showed that hiPSC-CMs derived from individuals with breast cancer who experienced doxorubicin-induced cardiotoxicity were consistently more sensitive to doxorubicin toxicity than hiPSC-CMs from patients who did not suffer from this side effect.
The present study will be based on, and extended from, our previous recent proof-of-concept work on biomarkers for late onset of doxorubicin-induced cardiotoxicity using human embryonic stem cell-(hESC)-CM assays. The results from our previous work, showing sensitivity of hESC-CM for late on-set cardiac toxicity, indicate the suitability of these systems for toxicity biomarker discovery and validation. To further strengthen the relevance and potential use of the test model, extended characterization of the cardiomyocytes is desirable. The possibly to study the effects of doxorubicin on a single cell level would give valuable characterization and knowledge of doxorubicin’s mechanisms.