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Cellular model systems to study cardiovascular injury from chemotherapy

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Abstract

In spite of all the efforts for generating efficient pharmacological treatment options for cancer patients, the unwanted side effect of these substances on the cardiovascular system is becoming a major issue for cancer survivors. The fast pacing oncology field necessitate the quest for more accurate and reliable preclinical screenings. hiPSCs derived cardiomyocytes, endothelial and vascular smooth muscle cells provide unlimited source of physiologically relevant cells that could be used in the screening platforms. Cells derived from hiPSCs can measure drug induced alterations to different aspect of the heart including electrophysiology, contractility and structure. In this review, we will give an overview of the different in vivo and in vitro preclinical drug safety screenings. In following sections, we will focus on hiPSCs derived cardiomyocytes, endothelial and vascular smooth muscle cells and present the current knowledge of the application of these cells in unicellular cardiotoxicity assays. In the final part, we will focus on cardiac organoids as multi cell type platform and their role in cardiotoxicity screening of the chemotherapeutic drugs.

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References

  1. Sorrentino MF et al (2012) 5-fluorouracil induced cardiotoxicity: review of the literature. Cardiol J 19(5):453–458

    Article  Google Scholar 

  2. Carver JR et al (2007) American Society of Clinical Oncology clinical evidence review on the ongoing care of adult cancer survivors: cardiac and pulmonary late effects. J ClinOncol 25(25):3991–4008

    Article  CAS  Google Scholar 

  3. Moslehi JJ, Deininger M (2015) Tyrosine kinase inhibitor-associated cardiovascular toxicity in chronic myeloid leukemia. J ClinOncol 33(35):4210–4218

    Article  CAS  Google Scholar 

  4. Han Y et al (2015) Cardiotoxicity evaluation of anthracyclines in zebrafish (Daniorerio). J ApplToxicol 35(3):241–252

    CAS  Google Scholar 

  5. Miranda CJ et al (2003) Hfe deficiency increases susceptibility to cardiotoxicity and exacerbates changes in iron metabolism induced by doxorubicin. Blood 102(7):2574–2580

    Article  CAS  Google Scholar 

  6. Zhang S et al (2012) Identification of the molecular basis of doxorubicin-induced cardiotoxicity. Nat Med 18(11):1639–1642

    Article  Google Scholar 

  7. Mercola M, Colas A, Willems E (2013) Induced pluripotent stem cells in cardiovascular drug discovery. Circ Res 112(3):534–548

    Article  CAS  Google Scholar 

  8. Del Rosario ME, Weachter R, Flaker GC (2010) Drug-induced QT prolongation and sudden death. Mo Med 107(1):53–58

    PubMed  PubMed Central  Google Scholar 

  9. Hoffmann P, Warner B (2006) Are hERG channel inhibition and QT interval prolongation all there is in drug-induced torsadogenesis? a review of emerging trends. J PharmacolToxicol Methods 53(2):87–105

    Article  CAS  Google Scholar 

  10. Fonoudi H et al (2020) Generating a cost-effective, weekend-free chemically defined human induced pluripotent stem cell (hiPSC) culture medium. CurrProtoc Stem Cell Biol 53(1):e110

    CAS  Google Scholar 

  11. Fonoudi H et al (2015) A universal and robust integrated platform for the scalable production of human cardiomyocytes from pluripotent stem cells. Stem Cells Transl Med 4(12):1482–1494

    Article  Google Scholar 

  12. Burridge PW et al (2014) Chemically defined generation of human cardiomyocytes. Nat Methods 11(8):855–860

    Article  CAS  Google Scholar 

  13. Burridge PW et al (2016) Human induced pluripotent stem cell-derived cardiomyocytes recapitulate the predilection of breast cancer patients to doxorubicin-induced cardiotoxicity. Nat Med 22(5):547–556

    Article  CAS  Google Scholar 

  14. Knowles DA et al (2018) Determining the genetic basis of anthracycline-cardiotoxicity by molecular response QTL mapping in induced cardiomyocytes. Elife. https://doi.org/10.7554/eLife.33480

    Article  PubMed  PubMed Central  Google Scholar 

  15. Maillet A et al (2016) Modeling doxorubicin-induced cardiotoxicity in human pluripotent stem cell derived-cardiomyocytes. Sci Rep 6:25333

    Article  CAS  Google Scholar 

  16. Necela BM et al (2017) The antineoplastic drug, trastuzumab, dysregulates metabolism in iPSC-derived cardiomyocytes. ClinTransl Med 6(1):5

    Google Scholar 

  17. Wang H et al (2019) Adaptation of human iPSC-derived cardiomyocytes to tyrosine kinase inhibitors reduces acute cardiotoxicity via metabolic reprogramming. Cell Syst 8(5):412–426.e7

    Article  CAS  Google Scholar 

  18. Sharma A et al (2018) Use of human induced pluripotent stem cell-derived cardiomyocytes to assess drug cardiotoxicity. Nat Protoc 13(12):3018–3041

    Article  CAS  Google Scholar 

  19. Hadzijusufovic E et al (2017) Nilotinib-induced vasculopathy: identification of vascular endothelial cells as a primary target site. Leukemia 31(11):2388–2397

    Article  CAS  Google Scholar 

  20. Zhang J et al (2019) A human pluripotent stem cell-based screen for smooth muscle cell differentiation and maturation identifies inhibitors of intimal hyperplasia. Stem Cell Reports 12(6):1269–1281

    Article  Google Scholar 

  21. Sa S et al (2017) Induced pluripotent stem cell model of pulmonary arterial hypertension reveals novel gene expression and patient specificity. Am J RespirCrit Care Med 195(7):930–941

    Article  CAS  Google Scholar 

  22. Safar ME (2018) Arterial stiffness as a risk factor for clinical hypertension. Nat Rev Cardiol 15(2):97–105

    Article  Google Scholar 

  23. Richards DJ et al (2017) Inspiration from heart development: Biomimetic development of functional human cardiac organoids. Biomaterials 142:112–123

    Article  CAS  Google Scholar 

  24. Giacomelli E et al (2010) Human iPSC derived cardiac stromal cells enhance maturation in 3D cardiac microtissues and reveal non-cardiomyocyte contributions to heart disease. Cell Stem Cell 26(6):862–879

    Article  Google Scholar 

  25. Polonchuk L et al (2017) Cardiac spheroids as promising in vitro models to study the human heart microenvironment. Sci Rep 7(1):7005

    Article  Google Scholar 

  26. Archer CR et al (2018) Characterization and validation of a human 3D cardiac microtissue for the assessment of changes in cardiac pathology. Sci Rep 8(1):10160

    Article  Google Scholar 

  27. Bergstrom G et al (2015) Stem cell derived in vivo-like human cardiac bodies in a microfluidic device for toxicity testing by beating frequency imaging. Lab Chip 15(15):3242–3249

    Article  Google Scholar 

  28. Mills RJ, Hudson JE (2019) Bioengineering adult human heart tissue: how close are we? APL Bioeng 3(1):010901

    Article  Google Scholar 

  29. Breckwoldt K et al (2017) Differentiation of cardiomyocytes and generation of human engineered heart tissue. Nat Protoc 12(6):1177–1197

    Article  CAS  Google Scholar 

  30. Mills RJ et al (2017) Functional screening in human cardiac organoids reveals a metabolic mechanism for cardiomyocyte cell cycle arrest. ProcNatlAcadSci USA 114(40):E8372–E8381

    Article  CAS  Google Scholar 

  31. Chen L, El-Sherif N, Boutjdir M (1999) Unitary current analysis of L-type Ca2+ channels in human fetal ventricular myocytes. J CardiovascElectrophysiol 10(5):692–700

    Article  CAS  Google Scholar 

  32. Cui N et al (2019) 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 23(7):4627–4639

    Article  CAS  Google Scholar 

  33. Mehta LS et al (2018) Cardiovascular disease and breast cancer: where these entities intersect: a scientific statement from the american heart association. Circulation 137(8):e30–e66

    Article  Google Scholar 

  34. Richards DJ et al (2020) Human cardiac organoids for the modelling of myocardial infarction and drug cardiotoxicity. Nat Biomed Eng 4(4):446–462

    Article  CAS  Google Scholar 

  35. Thomas CA et al (2017) Modeling of TREX1-dependent autoimmune disease using human stem cells highlights L1 accumulation as a source of neuroinflammation. Cell Stem Cell 21(3):319–331.e8

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

    Hananeh Fonoudi & Paul W. Burridge

  2. Center for Pharmacogenomics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

    Hananeh Fonoudi & Paul W. Burridge

Authors
  1. Hananeh Fonoudi
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  2. Paul W. Burridge
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Correspondence to Paul W. Burridge.

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Fonoudi, H., Burridge, P.W. Cellular model systems to study cardiovascular injury from chemotherapy. J Thromb Thrombolysis 51, 890–896 (2021). https://doi.org/10.1007/s11239-020-02299-x

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  • DOI: https://doi.org/10.1007/s11239-020-02299-x

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