Skip to main content

Advertisement

SpringerLink
Log in

Pluripotent Stem Cell Modeling of Anticancer Therapy–Induced Cardiotoxicity

  • Regenerative Medicine (SM Wu, Section Editor)
  • Published:
Current Cardiology Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

In this article, we review the different model systems based on human-induced pluripotent stem cell–derived cardiomyocytes (hiPSC-CMs) and how they have been applied to identify the cardiotoxic effects of anticancer therapies.

Recent Findings

Developments on 2D and 3D culture systems enabled the use of hiPSC-CMs as screening platforms for cardiotoxic effects of anticancer therapies such as anthracyclines, monoclonal antibodies, and tyrosine kinase inhibitors. Combined with computational approaches and higher throughput screening technologies, they have also enabled mechanistic studies and the search for cardioprotective strategies.

Summary

As the population ages and cancer treatments become more effective, the cardiotoxic effects of anticancer drugs become a bigger problem leading to an increased role of cardio-oncology. In the past decade, human-induced pluripotent stem cell–derived cardiomyocytes (hiPSC-CMs) have become an important platform for preclinical drug tests, elucidating mechanisms of action for drugs, and identifying cardioprotective pathways that could be further explored in the development of combined treatments. In this article, we highlight 2D and 3D model systems based on hiPSC-CMs that have been used to study the cardiotoxic effects of anticancer drugs, investigating their mechanisms of action and the potential for patient-specific prediction. We also present some of the important challenges and opportunities in the field, indicating possible future developments and how they could impact the landscape of cardio-oncology.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Piper SE, McDonagh TA. Chemotherapy-related cardiomyopathy. Eur Cardiol. 2015;10(1):19–24.

    PubMed  PubMed Central  Google Scholar 

  2. Ewer MS, Ewer SM. Cardiotoxicity of anticancer treatments. Nat Rev Cardiol. 2015;12(9):547–58.

    CAS  PubMed  Google Scholar 

  3. Bracken MB. Why animal studies are often poor predictors of human reactions to exposure. J R Soc Med. 2009;102(3):120–2.

    PubMed  PubMed Central  Google Scholar 

  4. Laco F, Woo TL, Zhong Q, Szmyd R, Ting S, Khan FJ, et al. Unraveling the inconsistencies of cardiac differentiation efficiency induced by the GSK3β inhibitor CHIR99021 in human pluripotent stem cells. Stem Cell Reports. 2018;10(6):1851–66.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Burridge PW, Matsa E, Shukla P, Lin ZC, Churko JM, Ebert AD, et al. Chemically defined generation of human cardiomyocytes. Nat Methods. 2014;11(8):855–60.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Lian X, Bao X, Al-Ahmad A, Liu J, Wu Y, Dong W, et al. Efficient differentiation of human pluripotent stem cells to endothelial progenitors via small-molecule activation of WNT signaling. Stem Cell Reports. 2014;3(5):804–16.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Burridge PW, Li YF, Matsa E, Wu H, Ong SG, Sharma A, et al. Human induced pluripotent stem cell-derived cardiomyocytes recapitulate the predilection of breast cancer patients to doxorubicin-induced cardiotoxicity. Nat Med. 2016;22(5):547–56.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Cui N, Wu F, Lu WJ, Bai R, Ke B, Liu T, et al. Doxorubicin-induced cardiotoxicity is maturation dependent due to the shift from topoisomerase IIα to IIβ in human stem cell derived cardiomyocytes. J Cell Mol Med. 2019;23(7):4627–39.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. • Knowles DA, Burrows CK, Blischak JD, Patterson KM, Serie DJ, Norton N, et al. Determining the genetic basis of anthracycline-cardiotoxicity by molecular response QTL mapping in induced cardiomyocytes. Elife. 2018;7:e33480 Findings from this larger scale study further validate the use of hiPSC-CMs as a screening platform for inter-individual differences in anthracycline-induced cardiotoxicity and the in vivo relevance of this model system to predict patient prognosis to therapy.

    PubMed  PubMed Central  Google Scholar 

  10. Holmgren G, Synnergren J, Bogestål Y, Améen C, Åkesson K, Holmgren S, et al. Identification of novel biomarkers for doxorubicin-induced toxicity in human cardiomyocytes derived from pluripotent stem cells. Toxicology. 2015;328:102–11.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Chaudhari U, Nemade H, Wagh V, Gaspar JA, Ellis JK, Srinivasan SP, et al. Identification of genomic biomarkers for anthracycline-induced cardiotoxicity in human iPSC-derived cardiomyocytes: an in vitro repeated exposure toxicity approach for safety assessment. Arch Toxicol. 2016;90(11):2763–77.

    CAS  PubMed  Google Scholar 

  12. Maillet A, Tan K, Chai X, Sadananda SN, Mehta A, Ooi J, et al. Modeling doxorubicin-induced cardiotoxicity in human pluripotent stem cell derived-cardiomyocytes. Sci Rep. 2016;6:25333.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Necela BM, Axenfeld BC, Serie DJ, Kachergus JM, Perez EA, Thompson EA, et al. The antineoplastic drug, trastuzumab, dysregulates metabolism in iPSC-derived cardiomyocytes. Clin Transl Med. 2017;6(1):5.

    PubMed  PubMed Central  Google Scholar 

  14. Kitani T, Ong SG, Lam CK, Rhee JW, Zhang JZ, Oikonomopoulos A, et al. Human-induced pluripotent stem cell model of trastuzumab-induced cardiac dysfunction in patients with breast cancer. Circulation. 2019;139(21):2451–65.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. De Lorenzo C, Paciello R, Riccio G, Rea D, Barbieri A, Coppola C, et al. Cardiotoxic effects of the novel approved anti-ErbB2 agents and reverse cardioprotective effects of ranolazine. Onco Targets Ther. 2018;11:2241–50.

    PubMed  PubMed Central  Google Scholar 

  16. Cohen JD, Babiarz JE, Abrams RM, Guo L, Kameoka S, Chiao E, et al. Use of human stem cell derived cardiomyocytes to examine sunitinib mediated cardiotoxicity and electrophysiological alterations. Toxicol Appl Pharmacol. 2011;257(1):74–83.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Wang H, Sheehan RP, Palmer AC, Everley RA, Boswell SA, Ron-Harel N, et al. Adaptation of human iPSC-derived cardiomyocytes to tyrosine kinase inhibitors reduces acute cardiotoxicity via metabolic reprogramming. Cell Syst. 2019;8(5):412–426.e7.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Sharma A, Burridge PW, McKeithan WL, Serrano R, Shukla P, Sayed N, et al. High-throughput screening of tyrosine kinase inhibitor cardiotoxicity with human induced pluripotent stem cells. Sci Transl Med. 2017;9(377):eaaf2584.

    PubMed  PubMed Central  Google Scholar 

  19. •• Sharma A, McKeithan WL, Serrano R, Kitani T, Burridge PW, Del Álamo JC, et al. Use of human induced pluripotent stem cell-derived cardiomyocytes to assess drug cardiotoxicity. Nat Protoc. 2018;13(12):3018–41 This protocol presents a useful platform to study the mechanisms of action of different anticancer therapies and to quantify their cardiotoxic responses in an easier to understand metric called “cardiac safety index” (CSI). Additionally, this same approach was used to investigate cardioprotective mechanisms in the context of TKI therapies in [18].

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Yan Y, Bejoy J, Xia J, Griffin K, Guan J, Li Y. Cell population balance of cardiovascular spheroids derived from human induced pluripotent stem cells. Sci Rep. 2019;9(1):1295.

    PubMed  PubMed Central  Google Scholar 

  21. Nugraha B, Buono MF, von Boehmer L, Hoerstrup SP, Emmert MY. Human cardiac organoids for disease modeling. Clin Pharmacol Ther. 2019;105(1):79–85.

    PubMed  Google Scholar 

  22. Bergström G, Christoffersson J, Schwanke K, Zweigerdt R, Mandenius CF. Stem cell derived in vivo-like human cardiac bodies in a microfluidic device for toxicity testing by beating frequency imaging. Lab Chip. 2015;15(15):3242–9.

    PubMed  Google Scholar 

  23. Polonchuk L, Chabria M, Badi L, Hoflack JC, Figtree G, Davies MJ, et al. Cardiac spheroids as promising in vitro models to study the human heart microenvironment. Sci Rep. 2017;7(1):7005.

    PubMed  PubMed Central  Google Scholar 

  24. Beauchamp P, Jackson CB, Ozhathil LC, Agarkova I, Galindo CL, Sawyer DB, et al. 3D co-culture of hiPSC-derived cardiomyocytes with cardiac fibroblasts improves tissue-like features of cardiac spheroids. Front Mol Biosci. 2020;7:14.

    PubMed  PubMed Central  Google Scholar 

  25. Archer CR, Sargeant R, Basak J, Pilling J, Barnes JR, Pointon A. Characterization and validation of a human 3D cardiac microtissue for the assessment of changes in cardiac pathology. Sci Rep. 2018;8(1):10160.

    PubMed  PubMed Central  Google Scholar 

  26. Truitt R, Mu A, Corbin EA, Vite A, Brandimarto J, Ky B, et al. Increased afterload augments sunitinib-induced cardiotoxicity in an engineered cardiac microtissue model. JACC Basic Transl Sci. 2018;3(2):265–76.

    PubMed  PubMed Central  Google Scholar 

  27. Huebsch N, Loskill P, Deveshwar N, Spencer CI, Judge LM, Mandegar MA, et al. Miniaturized iPS-cell-derived cardiac muscles for physiologically relevant drug response analyses. Sci Rep. 2016;6:24726.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Mannhardt I, Breckwoldt K, Letuffe-Brenière D, Schaaf S, Schulz H, Neuber C, et al. Human engineered heart tissue: analysis of contractile force. Stem Cell Reports. 2016;7(1):29–42.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Goldfracht I, Protze S, Shiti A, Setter N, Gruber A, Shaheen N, et al. Generating ring-shaped engineered heart tissues from ventricular and atrial human pluripotent stem cell-derived cardiomyocytes. Nat Commun. 2020;11(1):75.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Mills RJ, Titmarsh DM, Koenig X, Parker BL, Ryall JG, Quaife-Ryan GA, et al. Functional screening in human cardiac organoids reveals a metabolic mechanism for cardiomyocyte cell cycle arrest. Proc Natl Acad Sci U S A. 2017;114(40):E8372–81.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Mills RJ, Parker BL, Quaife-Ryan GA, Voges HK, Needham EJ, Bornot A, et al. Drug screening in human PSC-cardiac organoids identifies pro-proliferative compounds acting via the mevalonate pathway. Cell Stem Cell. 2019;24(6):895–907.e6.

    CAS  PubMed  Google Scholar 

  32. MacQueen LA, Sheehy SP, Chantre CO, Zimmerman JF, Pasqualini FS, Liu X, et al. A tissue-engineered scale model of the heart ventricle. Nat Biomed Eng. 2018;2(12):930–41.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Wang L, Yu P, Zhou B, Song J, Li Z, Zhang M, et al. Single-cell reconstruction of the adult human heart during heart failure and recovery reveals the cellular landscape underlying cardiac function. Nat Cell Biol. 2020;22(1):108–19.

    CAS  PubMed  Google Scholar 

  34. Kurokawa YK, Shang MR, Yin RT, George SC. Modeling trastuzumab-related cardiotoxicity in vitro using human stem cell-derived cardiomyocytes. Toxicol Lett. 2018;285:74–80.

    CAS  PubMed  Google Scholar 

  35. Amano Y, Nishiguchi A, Matsusaki M, Iseoka H, Miyagawa S, Sawa Y, et al. Development of vascularized iPSC derived 3D-cardiomyocyte tissues by filtration layer-by-layer technique and their application for pharmaceutical assays. Acta Biomater. 2016;33:110–21.

    CAS  PubMed  Google Scholar 

  36. Takeda M, Miyagawa S, Fukushima S, Saito A, Ito E, Harada A, et al. Development of in vitro drug-induced cardiotoxicity assay by using three-dimensional cardiac tissues derived from human induced pluripotent stem cells. Tissue Eng Part C Methods. 2018;24(1):56–67.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Weng KC, Kurokawa YK, Hajek BS, Paladin JA, Shirure VS, George SC. Human induced pluripotent stem-cardiac-endothelial-tumor-on-a-chip to assess anticancer efficacy and cardiotoxicity. Tissue Eng Part C Methods. 2020;26(1):44–55.

    CAS  PubMed  Google Scholar 

  38. Oleaga C, Bernabini C, Smith AS, Srinivasan B, Jackson M, McLamb W, et al. Multi-organ toxicity demonstration in a functional human in vitro system composed of four organs. Sci Rep. 2016;6:20030.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Kamei K-i, Kato Y, Hirai Y, Ito S, Satoh J, Oka A, et al. Integrated heart/cancer on a chip to reproduce the side effects of anti-cancer drugs in vitro. RSC Adv. 2017;7(58):36777–86.

    CAS  Google Scholar 

  40. Zhang YS, Aleman J, Shin SR, Kilic T, Kim D, Shaegh SAM, et al. Multisensor-integrated organs-on-chips platform for automated and continual in situ monitoring of organoid behaviors. Proc Natl Acad Sci U S A. 2017;114(12):E2293–302.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Ronaldson-Bouchard K, Vunjak-Novakovic G. Organs-on-a-chip: a fast track for engineered human tissues in drug development. Cell Stem Cell. 2018;22(3):310–24.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Lind JU, Yadid M, Perkins I, O’Connor BB, Eweje F, Chantre CO, et al. Cardiac microphysiological devices with flexible thin-film sensors for higher-throughput drug screening. Lab Chip. 2017;17(21):3692–703.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Lind JU, Busbee TA, Valentine AD, Pasqualini FS, Yuan H, Yadid M, et al. Instrumented cardiac microphysiological devices via multimaterial three-dimensional printing. Nat Mater. 2017;16(3):303–8.

    CAS  PubMed  Google Scholar 

  44. Zhang YS, Arneri A, Bersini S, Shin SR, Zhu K, Goli-Malekabadi Z, et al. Bioprinting 3D microfibrous scaffolds for engineering endothelialized myocardium and heart-on-a-chip. Biomaterials. 2016;110:45–59.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 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. 2012;130(1):117–31.

    CAS  PubMed  Google Scholar 

  46. Ebert A, Joshi AU, Andorf S, Dai Y, Sampathkumar S, Chen H, et al. Proteasome-dependent regulation of distinct metabolic states during long-term culture of human iPSC-derived cardiomyocytes. Circ Res. 2019;125(1):90–103.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Correia C, Koshkin A, Duarte P, Hu D, Teixeira A, Domian I, et al. Distinct carbon sources affect structural and functional maturation of cardiomyocytes derived from human pluripotent stem cells. Sci Rep. 2017;7(1):8590.

    PubMed  PubMed Central  Google Scholar 

  48. Hu D, Linders A, Yamak A, Correia C, Kijlstra JD, Garakani A, et al. Metabolic maturation of human pluripotent stem cell-derived cardiomyocytes by inhibition of HIF1α and LDHA. Circ Res. 2018;123(9):1066–79.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Yang X, Rodriguez ML, Leonard A, Sun L, Fischer KA, Wang Y, et al. Fatty acids enhance the maturation of cardiomyocytes derived from human pluripotent stem cells. Stem Cell Reports. 2019;13(4):657–68.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Ribeiro MC, Tertoolen LG, Guadix JA, Bellin M, Kosmidis G, D’Aniello C, et al. Functional maturation of human pluripotent stem cell derived cardiomyocytes in vitro--correlation between contraction force and electrophysiology. Biomaterials. 2015;51:138–50.

    CAS  PubMed  Google Scholar 

  51. Huh D, Torisawa Y-S, Hamilton GA, Kim HJ, Ingber DE. Microengineered physiological biomimicry: organs-on-chips. Lab Chip. 2012;12(12):2156.

    CAS  PubMed  Google Scholar 

  52. Besser RR, Ishahak M, Mayo V, Carbonero D, Claure I, Agarwal A. Engineered microenvironments for maturation of stem cell derived cardiac myocytes. Theranostics. 2018;8(1):124–40.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Herron TJ, Rocha AM, Campbell KF, Ponce-Balbuena D, Willis BC, Guerrero-Serna G, et al. Extracellular matrix-mediated maturation of human pluripotent stem cell-derived cardiac monolayer structure and electrophysiological function. Circ Arrhythm Electrophysiol. 2016;9(4):e003638.

    CAS  PubMed  Google Scholar 

  54. da Rocha AM, Campbell K, Mironov S, Jiang J, Mundada L, Guerrero-Serna G, et al. hiPSC-CM monolayer maturation state determines drug responsiveness in high throughput pro-arrhythmia screen. Sci Rep. 2017;7(1):13834.

    PubMed  PubMed Central  Google Scholar 

  55. Li J, Minami I, Shiozaki M, Yu L, Yajima S, Miyagawa S, et al. Human pluripotent stem cell-derived cardiac tissue-like constructs for repairing the infarcted myocardium. Stem Cell Reports. 2017;9(5):1546–59.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Bray MA, Sheehy SP, Parker KK. Sarcomere alignment is regulated by myocyte shape. Cell Motil Cytoskeleton. 2008;65(8):641–51.

    PubMed  PubMed Central  Google Scholar 

  57. Carson D, Hnilova M, Yang X, Nemeth CL, Tsui JH, Smith AS, et al. Nanotopography-induced structural anisotropy and sarcomere development in human cardiomyocytes derived from induced pluripotent stem cells. ACS Appl Mater Interfaces. 2016;8(34):21923–32.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Bray MA, Adams WJ, Geisse NA, Feinberg AW, Sheehy SP, Parker KK. Nuclear morphology and deformation in engineered cardiac myocytes and tissues. Biomaterials. 2010;31(19):5143–50.

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Ulmer BM, Eschenhagen T. Human pluripotent stem cell-derived cardiomyocytes for studying energy metabolism. Biochim Biophys Acta Mol Cell Res. 1867;2020(3):118471.

    Google Scholar 

  60. Huethorst E, Hortigon M, Zamora-Rodriguez V, Reynolds PM, Burton F, Smith G, et al. Enhanced human-induced pluripotent stem cell derived cardiomyocyte maturation using a dual microgradient substrate. ACS Biomater Sci Eng. 2016;2(12):2231–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Khan M, Xu Y, Hua S, Johnson J, Belevych A, Janssen PM, et al. Evaluation of changes in morphology and function of human induced pluripotent stem cell derived cardiomyocytes (HiPSC-CMs) cultured on an aligned-nanofiber cardiac patch. PLoS One. 2015;10(5):e0126338.

    PubMed  PubMed Central  Google Scholar 

  62. Lyra-Leite DM, Andres AM, Petersen AP, Ariyasinghe NR, Cho N, Lee JA, et al. Mitochondrial function in engineered cardiac tissues is regulated by extracellular matrix elasticity and tissue alignment. Am J Physiol Heart Circ Physiol. 2017;313(4):H757–67. https://doi.org/10.1152/ajpheart.00290.2017.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Lyra-Leite DM, Andres AM, Cho N, Petersen AP, Ariyasinghe NR, Kim SS, et al. Matrix-guided control of mitochondrial function in cardiac myocytes. Acta Biomater. 2019;97:281–95.

    CAS  PubMed  Google Scholar 

  64. Eldridge S, Guo L, Mussio J, Furniss M, Hamre J, Davis M. Examining the protective role of ErbB2 modulation in human-induced pluripotent stem cell-derived cardiomyocytes. Toxicol Sci. 2014;141(2):547–59.

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmacology, Northwestern University Feinberg School of Medicine, 320 E Superior St, Searle 8-525, Chicago, IL, 60611, USA

    Davi M. Lyra-Leite & Paul W. Burridge

  2. Center for Pharmacogenomics, Northwestern University Feinberg School of Medicine, 320 E Superior St, Searle 8-525, Chicago, IL, 60611, USA

    Davi M. Lyra-Leite & Paul W. Burridge

Authors
  1. Davi M. Lyra-Leite
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Paul W. Burridge
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Paul W. Burridge.

Ethics declarations

Conflict of Interest

Davi M. Lyra-Leite and Paul W. Burridge declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the Topical Collection on Regenerative Medicine

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lyra-Leite, D.M., Burridge, P.W. Pluripotent Stem Cell Modeling of Anticancer Therapy–Induced Cardiotoxicity. Curr Cardiol Rep 22, 56 (2020). https://doi.org/10.1007/s11886-020-01325-x

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11886-020-01325-x

Keywords

Search

Navigation