Human induced pluripotent stem cell–derived cardiomyocytes recapitulate the predilection of breast cancer patients to doxorubicin-induced cardiotoxicity

Abstract

Doxorubicin is an anthracycline chemotherapy agent effective in treating a wide range of malignancies, but it causes a dose-related cardiotoxicity that can lead to heart failure in a subset of patients. At present, it is not possible to predict which patients will be affected by doxorubicin-induced cardiotoxicity (DIC). Here we demonstrate that patient-specific human induced pluripotent stem cell–derived cardiomyocytes (hiPSC-CMs) can recapitulate the predilection to DIC of individual patients at the cellular level. hiPSC-CMs derived from individuals with breast cancer who experienced DIC were consistently more sensitive to doxorubicin toxicity than hiPSC-CMs from patients who did not experience DIC, with decreased cell viability, impaired mitochondrial and metabolic function, impaired calcium handling, decreased antioxidant pathway activity, and increased reactive oxygen species production. Taken together, our data indicate that hiPSC-CMs are a suitable platform to identify and characterize the genetic basis and molecular mechanisms of DIC.

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Figure 1: Assessment of in vitro doxorubicin-induced cardiotoxicity in patient-specific hiPSC-CMs.
Figure 2: Assessment of the effects of doxorubicin on DNA damage, calcium handling, and whole-cell oxidative stress in patient-specific hiPSC-CMs.
Figure 3: The effects of doxorubicin on oxidative stress in patient-specific hiPSC-CMs.
Figure 4: Modulation of gene expression in hESC-CMs and hiPSC-CMs by doxorubicin.
Figure 5: Assessment of baseline mitochondrial function in patient-specific hiPSC-CMs.
Figure 6: Schematic of the effects of doxorubicin on patient-specific hiPSC-CMs in relationship to established DIC pathways.

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Acknowledgements

We thank J. Odegaard for analysis of teratoma slides. This work was supported by the US National Institutes of Health (NIH) grants K99/R00 HL121177 (P.W.B.), R21 HL123655 (D.B.), R01 LM05652 (R.B.A.), R01 GM102365 (R.B.A.), R24 GM61374 (R.B.A.), R01 HL123968 (J.C.W.), R01 HL126527 (J.C.W.), R01 HL128170 (J.C.W.), R01 HL130020 (J.C.W.), R01 AR063963 (H.M.B.), R01 AG020961 (H.M.B.), R21 AG04481501 (H.M.B.), and R01 NS089533 (H.M.B.); the American Heart Association (AHA) grants AHA 14BGIA20480329 (P.W.B.), AHA 13POST14480004 (A.C.C.), and AHA 13EIA14420025 (J.C.W.); a Dixon Translational Research Grant Young Investigator Award (P.W.B.), the California Institute of Regenerative Medicine (CIRM) awards IT1-06596 (J.C.W.), TR3-05501 (H.M.B.) and RB5-07469 (H.M.B.); the Muscular Dystrophy Association grant 4320 (H.M.B.); the Baxter Foundation (H.M.B.); and a Burroughs Wellcome Fund Innovation in Regulatory Science Award (J.C.W.).

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P.W.B. performed project planning, experimental design, hiPSC reprogramming, cell culture, characterizations, differentiation, cardiotoxicity analysis, flow cytometry, data analysis, and wrote the manuscript; Y.F.L. performed computational analyses of microarray and RNA-seq data, gene enrichment analysis, and wrote part of the manuscript; E.M. and A.H. performed cell culture; E.M. and A.S. performed immunohistochemistry; H.W. performed Ca2+ imaging; P.W.B., S.-G.O., A.C.C., M.J.C., and A.D.E. performed Seahorse analysis; S.-G.O. performed mitochondrial analysis; J.W.K., M.L.T., and R.M.W. recruited patients; H.M.B., D.B., R.B.A., and J.C.W. helped in manuscript preparation; J.C.W. and P.W.B. provided conceptual design of the study and funding support.

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Correspondence to Paul W Burridge or Joseph C Wu.

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P.W.B. is a shareholder in Stem Cell Theranostics, and J.C.W. is a cofounder and shareholder in Stem Cell Theranostics.

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Burridge, P., Li, Y., Matsa, E. et al. Human induced pluripotent stem cell–derived cardiomyocytes recapitulate the predilection of breast cancer patients to doxorubicin-induced cardiotoxicity. Nat Med 22, 547–556 (2016). https://doi.org/10.1038/nm.4087

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