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

Nature Medicine volume 22, pages 547–556 (2016)Cite this article

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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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References

  1. Lipshultz, S.E., Franco, V.I., Miller, T.L., Colan, S.D. & Sallan, S.E. Cardiovascular disease in adult survivors of childhood cancer. Annu. Rev. Med. 66, 161–176 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Giordano, S.H., Lin, Y.-L., Kuo, Y.F., Hortobagyi, G.N. & Goodwin, J.S. Decline in the use of anthracyclines for breast cancer. J. Clin. Oncol. 30, 2232–2239 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Lefrak, E.A., Pitha, J., Rosenheim, S. & Gottlieb, J.A. A clinicopathologic analysis of Adriamycin cardiotoxicity. Cancer 32, 302–314 (1973).

    Article  CAS  PubMed  Google Scholar 

  4. Von Hoff, D.D. et al. Risk factors for doxorubicin-induced congestive heart failure. Ann. Intern. Med. 91, 710–717 (1979).

    Article  CAS  PubMed  Google Scholar 

  5. Swain, S.M., Whaley, F.S. & Ewer, M.S. Congestive heart failure in patients treated with doxorubicin: a retrospective analysis of three trials. Cancer 97, 2869–2879 (2003).

    Article  CAS  PubMed  Google Scholar 

  6. Kremer, L.C.M., van der Pal, H.J.H., Offringa, M., Van Dalen, E.C. & Voûte, P.A. Frequency and risk factors of subclinical cardiotoxicity after anthracycline therapy in children: a systematic review. Ann. Oncol. 13, 819–829 (2002).

    Article  CAS  PubMed  Google Scholar 

  7. Shakir, D.K. & Rasul, K.I. Chemotherapy-induced cardiomyopathy: pathogenesis, monitoring, and management. J. Clin. Med. Res. 1, 8–12 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Bernstein, D. & Burridge, P. Patient-specific pluripotent stem cells in doxorubicin cardiotoxicity: a new window into personalized medicine. Prog. Pediatr. Cardiol. 37, 23–27 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  9. Lipshultz, S.E., Cochran, T.R., Franco, V.I. & Miller, T.L. Treatment-related cardiotoxicity in survivors of childhood cancer. Nat. Rev. Clin. Oncol. 10, 697–710 (2013).

    Article  CAS  PubMed  Google Scholar 

  10. Granger, C.B. Prediction and prevention of chemotherapy-induced cardiomyopathy: can it be done? Circulation 114, 2432–2433 (2006).

    Article  PubMed  Google Scholar 

  11. Deavall, D.G., Martin, E.A., Horner, J.M. & Roberts, R. Drug-induced oxidative stress and toxicity. J. Toxicol. 2012, 645460 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Zhang, S. et al. Identification of the molecular basis of doxorubicin-induced cardiotoxicity. Nat. Med. 18, 1639–1642 (2012).

    Article  PubMed  CAS  Google Scholar 

  13. Khiati, S. et al. Mitochondrial topoisomerase I (Top1mt) is a novel limiting factor of doxorubicin cardiotoxicity. Clin. Cancer Res. 20, 4873–4881 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Hanna, A.D., Lam, A., Tham, S., Dulhunty, A.F. & Beard, N.A. Adverse effects of doxorubicin and its metabolic product on cardiac RyR2 and SERCA2A. Mol. Pharmacol. 86, 438–449 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Goormaghtigh, E., Brasseur, R., Huart, P. & Ruysschaert, J.M. Study of the Adriamycin–cardiolipin complex structure using attenuated total-reflection infrared spectroscopy. Biochemistry 26, 1789–1794 (1987).

    Article  CAS  PubMed  Google Scholar 

  16. Ichikawa, Y. et al. Cardiotoxicity of doxorubicin is mediated through mitochondrial iron accumulation. J. Clin. Invest. 124, 617–630 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Holmberg, S.R. & Williams, A.J. Patterns of interaction between anthraquinone drugs and the calcium-release channel from cardiac sarcoplasmic reticulum. Circ. Res. 67, 272–283 (1990).

    Article  CAS  PubMed  Google Scholar 

  18. Burridge, P.W. et al. Modeling cardiovascular diseases with patient-specific human pluripotent stem cell–derived cardiomyocytes. Methods Mol. Biol. 1353, 119–130 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Cahan, P. & Daley, G.Q. Origins and implications of pluripotent stem cell variability and heterogeneity. Nat. Rev. Mol. Cell Biol. 14, 357–368 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Peterson, S.E. & Loring, J.F. Genomic instability in pluripotent stem cells: implications for clinical applications. J. Biol. Chem. 289, 4578–4584 (2014).

    Article  CAS  PubMed  Google Scholar 

  21. Burridge, P.W. et al. Chemically defined generation of human cardiomyocytes. Nat. Methods 11, 855–860 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Burridge, P.W., Holmström, A. & Wu, J.C. Chemically defined culture and cardiomyocyte differentiation of human pluripotent stem cells. Curr. Protoc. Hum. Genet. 87, 21.3 (2015).

    Google Scholar 

  23. Rana, P., Anson, B., Engle, S. & Will, Y. Characterization of human induced pluripotent stem cell–derived cardiomyocytes: bioenergetics and utilization in safety screening. Toxicol. Sci. 130, 117–131 (2012).

    Article  CAS  PubMed  Google Scholar 

  24. Yang, X. et al. Triiodo-L-thyronine promotes the maturation of human cardiomyocytes derived from induced pluripotent stem cells. J. Mol. Cell. Cardiol. 72, 296–304 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Robert, J. et al. Comparative pharmacokinetics and metabolism of doxorubicin and epirubicin in patients with metastatic breast cancer. Cancer Treat. Rep. 69, 633–640 (1985).

    CAS  PubMed  Google Scholar 

  26. Bramwell, V.H.C. et al. Safety and efficacy of the multidrug-resistance inhibitor biricodar (VX-710) with concurrent doxorubicin in patients with anthracycline-resistant advanced soft tissue sarcoma. Clin. Cancer Res. 8, 383–393 (2002).

    CAS  PubMed  Google Scholar 

  27. Berdichevski, A. et al. TVP1022 protects neonatal rat ventricular myocytes against doxorubicin-induced functional derangements. J. Pharmacol. Exp. Ther. 332, 413–420 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Ito, H. et al. Doxorubicin selectively inhibits muscle gene expression in cardiac muscle cells in vivo and in vitro. Proc. Natl. Acad. Sci. USA 87, 4275–4279 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Ruan, Y. et al. SIRT1 suppresses doxorubicin-induced cardiotoxicity by regulating the oxidative stress and p38MAPK pathways. Cell. Physiol. Biochem. 35, 1116–1124 (2015).

    Article  CAS  PubMed  Google Scholar 

  30. Lim, C.C. et al. Anthracyclines induce calpain-dependent titin proteolysis and necrosis in cardiomyocytes. J. Biol. Chem. 279, 8290–8299 (2004).

    Article  CAS  PubMed  Google Scholar 

  31. Chen, B. et al. Disruption of a GATA4–ANKRD1 signaling axis in cardiomyocytes leads to sarcomere disarray: implications for anthracycline cardiomyopathy. PLoS One 7, e35743 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Doroshow, J.H. Effect of anthracycline antibiotics on oxygen radical formation in rat heart. Cancer Res. 43, 460–472 (1983).

    CAS  PubMed  Google Scholar 

  33. Shi, Y., Moon, M., Dawood, S., McManus, B. & Liu, P.P. Mechanisms and management of doxorubicin cardiotoxicity. Herz 36, 296–305 (2011).

    Article  CAS  PubMed  Google Scholar 

  34. Xu, X., Persson, H.L. & Richardson, D.R. Molecular pharmacology of the interaction of anthracyclines with iron. Mol. Pharmacol. 68, 261–271 (2005).

    Article  CAS  PubMed  Google Scholar 

  35. Venditti, P., Balestrieri, M., De Leo, T. & Di Meo, S. Free radical involvement in doxorubicin-induced electrophysiological alterations in rat papillary muscle fibers. Cardiovasc. Res. 38, 695–702 (1998).

    Article  CAS  PubMed  Google Scholar 

  36. Swain, S.M. et al. Cardioprotection with dexrazoxane for doxorubicin-containing therapy in advanced breast cancer. J. Clin. Oncol. 15, 1318–1332 (1997).

    Article  CAS  PubMed  Google Scholar 

  37. Deng, S. et al. The catalytic topoisomerase II inhibitor dexrazoxane induces DNA breaks, ATF3, and the DNA damage response in cancer cells. Br. J. Pharmacol. 172, 2246–2257 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Farshid, A.A. et al. Effects of histidine and N-acetylcysteine on doxorubicin-induced cardiomyopathy in rats. Cardiovasc. Toxicol. 14, 153–161 (2014).

    Article  CAS  PubMed  Google Scholar 

  39. Engreitz, J.M., Daigle, B.J. Jr., Marshall, J.J. & Altman, R.B. Independent component analysis: mining microarray data for fundamental human gene expression modules. J. Biomed. Inform. 43, 932–944 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Thorn, C.F. et al. Doxorubicin pathways: pharmacodynamics and adverse effects. Pharmacogenet. Genomics 21, 440–446 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Hussner, J. et al. Regulation of interferon-inducible proteins by doxorubicin via interferon-γ–Janus tyrosine kinase–signal transducer and activator of transcription signaling in tumor cells. Mol. Pharmacol. 81, 679–688 (2012).

    Article  CAS  PubMed  Google Scholar 

  42. Zhu, W., Zhang, W., Shou, W. & Field, L.J. p53 inhibition exacerbates late-stage anthracycline cardiotoxicity. Cardiovasc. Res. 103, 81–89 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Arts-de Jong, M., Maas, A.H.E.M., Massuger, L.F., Hoogerbrugge, N. & de Hullu, J.A. BRCA1/2 mutation carriers are potentially at higher cardiovascular risk. Crit. Rev. Oncol. Hematol. 91, 159–171 (2014).

    Article  CAS  PubMed  Google Scholar 

  44. Doroshow, J.H., Locker, G.Y. & Myers, C.E. Enzymatic defenses of the mouse heart against reactive oxygen metabolites: alterations produced by doxorubicin. J. Clin. Invest. 65, 128–135 (1980).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Torti, S.V., Akimoto, H., Lin, K., Billingham, M.E. & Torti, F.M. Selective inhibition of muscle gene expression by oxidative stress in cardiac cells. J. Mol. Cell. Cardiol. 30, 1173–1180 (1998).

    Article  CAS  PubMed  Google Scholar 

  46. Naidu, S.R., Love, I.M., Imbalzano, A.N., Grossman, S.R. & Androphy, E.J. The SWI/SNF chromatin remodeling subunit BRG1 is a critical regulator of p53 necessary for proliferation of malignant cells. Oncogene 28, 2492–2501 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Visscher, H. et al. CPNDS Consortium. Validation of variants in SLC28A3 and UGT1A6 as genetic markers predictive of anthracycline-induced cardiotoxicity in children. Pediatr. Blood Cancer 60, 1375–1381 (2013).

    Article  CAS  PubMed  Google Scholar 

  48. Lebrecht, D., Kokkori, A., Ketelsen, U.-P., Setzer, B. & Walker, U.A. Tissue-specific mtDNA lesions and radical-associated mitochondrial dysfunction in human hearts exposed to doxorubicin. J. Pathol. 207, 436–444 (2005).

    Article  CAS  PubMed  Google Scholar 

  49. Octavia, Y. et al. Doxorubicin-induced cardiomyopathy: from molecular mechanisms to therapeutic strategies. J. Mol. Cell. Cardiol. 52, 1213–1225 (2012).

    Article  CAS  PubMed  Google Scholar 

  50. Denning, C. et al. Cardiomyocytes from human pluripotent stem cells: from laboratory curiosity to industrial biomedical platform. Biochim. Biophys. Acta http://dx.doi:10.1016/j.bbamcr.2015.10.014 (2015).

  51. Zhu, R. et al. Physical developmental cues for the maturation of human pluripotent stem cell–derived cardiomyocytes. Stem Cell Res. Ther. 5, 117 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  52. David, R. & Franz, W.M. From pluripotency to distinct cardiomyocyte subtypes. Physiology (Bethesda) 27, 119–129 (2012).

    CAS  Google Scholar 

  53. Mathur, A. et al. Human iPSC-based cardiac microphysiological system for drug-screening applications. Sci. Rep. 5, 8883 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Mercola, M., Colas, A. & Willems, E. Induced pluripotent stem cells in cardiovascular drug discovery. Circ. Res. 112, 534–548 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Brown, S.-A., Sandhu, N. & Herrmann, J. Systems biology approaches to adverse drug effects: the example of cardio-oncology. Nat. Rev. Clin. Oncol. 12, 718–731 (2015).

    Article  CAS  PubMed  Google Scholar 

  56. Aminkeng, F. et al. A coding variant in RARG confers susceptibility to anthracycline-induced cardiotoxicity in childhood cancer. Nat. Genet. 47, 1079–1084 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Vejpongsa, P. & Yeh, E.T.H. Prevention of anthracycline-induced cardiotoxicity: challenges and opportunities. J. Am. Coll. Cardiol. 64, 938–945 (2014).

    Article  CAS  PubMed  Google Scholar 

  58. Kim, H.D., Kim, C.H., Rah, B.J., Chung, H.I. & Shim, T.S. Quantitative study on the relation between structural and functional properties of the hearts from three different mammals. Anat. Rec. 238, 199–206 (1994).

    Article  CAS  PubMed  Google Scholar 

  59. Hattori, F. et al. Nongenetic method for purifying stem cell–derived cardiomyocytes. Nat. Methods 7, 61–66 (2010).

    Article  CAS  PubMed  Google Scholar 

  60. Melkoumian, Z. et al. Synthetic peptide-acrylate surfaces for long-term self-renewal and cardiomyocyte differentiation of human embryonic stem cells. Nat. Biotechnol. 28, 606–610 (2010).

    Article  CAS  PubMed  Google Scholar 

  61. Chen, G. et al. Chemically defined conditions for human iPSC derivation and culture. Nat. Methods 8, 424–429 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Fusaki, N., Ban, H., Nishiyama, A., Saeki, K. & Hasegawa, M. Efficient induction of transgene-free human pluripotent stem cells using a vector based on Sendai virus, an RNA virus that does not integrate into the host genome. Proc. Jpn. Acad., Ser. B, Phys. Biol. Sci. 85, 348–362 (2009).

    Article  CAS  Google Scholar 

  63. Mali, P. et al. Butyrate greatly enhances derivation of human induced pluripotent stem cells by promoting epigenetic remodeling and the expression of pluripotency-associated genes. Stem Cells 28, 713–720 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Thomson, J.A. et al. Embryonic stem cell lines derived from human blastocysts. Science 282, 1145–1147 (1998).

    Article  CAS  PubMed  Google Scholar 

  65. Maddah, M. et al. A non-invasive platform for functional characterization of stem cell–derived cardiomyocytes with applications in cardiotoxicity testing. Stem Cell Rep. 4, 621–631 (2015).

    Article  CAS  Google Scholar 

  66. Huang, X. & Darzynkiewicz, Z. Cytometric assessment of histone H2AX phosphorylation: a reporter of DNA damage. Methods Mol. Biol. 314, 73–80 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Mukhopadhyay, P. et al. Simultaneous detection of apoptosis and mitochondrial superoxide production in live cells by flow cytometry and confocal microscopy. Nat. Protoc. 2, 2295–2301 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Irizarry, R.A. et al. Exploration, normalization, and summaries of high-density oligonucleotide array probe level data. Biostatistics 4, 249–264 (2003).

    Article  PubMed  Google Scholar 

  69. Bolstad, B.M., Irizarry, R.A., Astrand, M. & Speed, T.P. A comparison of normalization methods for high-density oligonucleotide array data based on variance and bias. Bioinformatics 19, 185–193 (2003).

    Article  CAS  PubMed  Google Scholar 

  70. Kim, D. et al. TopHat2: accurate alignment of transcriptomes in the presence of insertions, deletions, and gene fusions. Genome Biol. 14, R36 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  71. Trapnell, C. et al. Differential gene and transcript expression analysis of RNA-seq experiments with TopHat and Cufflinks. Nat. Protoc. 7, 562–578 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Li, H. et al. The sequence alignment–map format and SAMtools. Bioinformatics 25, 2078–2079 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  73. Cingolani, P. et al. A program for annotating and predicting the effects of single-nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strain w1118;iso-2;iso-3. Fly (Austin) 6, 80–92 (2012).

    Article  CAS  Google Scholar 

  74. Robinson, J.T. et al. Integrative genomics viewer. Nat. Biotechnol. 29, 24–26 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Hyvärinen, A. & Oja, E. Independent component analysis: algorithms and applications. Neural Netw. 13, 411–430 (2000).

    Article  PubMed  Google Scholar 

  76. Lee, S.-I. & Batzoglou, S. Application of independent component analysis to microarrays. Genome Biol. 4, R76 (2003).

    Article  PubMed  PubMed Central  Google Scholar 

  77. Alexa, A., Rahnenführer, J. & Lengauer, T. Improved scoring of functional groups from gene expression data by de-correlating GO graph structure. Bioinformatics 22, 1600–1607 (2006).

    Article  CAS  PubMed  Google Scholar 

  78. Gerstein, M.B. et al. Architecture of the human regulatory network derived from ENCODE data. Nature 489, 91–100 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Barrett, T. et al. NCBI GEO: archive for functional genomics data sets—update. Nucleic Acids Res. 41, D991–D995 (2013).

    Article  CAS  PubMed  Google Scholar 

Download references

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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Authors and Affiliations

  1. Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, USA

    Paul W Burridge, Elena Matsa, Haodi Wu, Sang-Ging Ong, Arun Sharma, Alexandra Holmström, Alex C Chang, Antje D Ebert, Joshua W Knowles, Ronald M Witteles, Helen M Blau, Daniel Bernstein & Joseph C Wu

  2. Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA

    Paul W Burridge, Elena Matsa, Haodi Wu, Sang-Ging Ong, Arun Sharma, Alexandra Holmström, Alex C Chang, Antje D Ebert, Helen M Blau & Joseph C Wu

  3. Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California, USA

    Paul W Burridge, Elena Matsa, Haodi Wu, Sang-Ging Ong, Arun Sharma, Alexandra Holmström, Antje D Ebert, Joshua W Knowles, Ronald M Witteles & Joseph C Wu

  4. Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA

    Paul W Burridge

  5. Center for Pharmacogenomics, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA

    Paul W Burridge

  6. Stanford Genome Technology Center, Stanford University School of Medicine, Stanford, California, USA

    Yong Fuga Li

  7. Department of Bioengineering, Stanford University School of Medicine, Stanford, California, USA

    Yong Fuga Li & Russ B Altman

  8. Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California, USA

    Alex C Chang & Helen M Blau

  9. Department of Pediatrics, Division of Cardiology, Stanford University School of Medicine, Stanford, California, USA

    Michael J Coronado & Daniel Bernstein

  10. Department of Medicine, Division of Oncology, Stanford University School of Medicine, Stanford, California, USA

    Melinda L Telli

  11. Department of Genetics, Stanford University School of Medicine, Stanford, California, USA

    Russ B Altman

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Contributions

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.

Corresponding authors

Correspondence to Paul W Burridge or Joseph C Wu.

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Competing interests

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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