Supplementary Materials

Supplementary Material for:

High-throughput screening of tyrosine kinase inhibitor cardiotoxicity with human induced pluripotent stem cells

Arun Sharma, Paul W. Burridge, Wesley L. McKeithan, Ricardo Serrano, Praveen Shukla, Nazish Sayed, Jared M. Churko, Tomoya Kitani, Haodi Wu, Alexandra Holmström, Elena Matsa, Yuan Zhang, Anusha Kumar, Alice C. Fan, Juan C. del Álamo, Sean M. Wu, Javid J. Moslehi, Mark Mercola, Joseph C. Wu*

*Corresponding author. Email: joewu{at}stanford.edu

Published 15 February 2017, Sci. Transl. Med. 9, eaaf2584 (2017)
DOI: 10.1126/scitranslmed.aaf2584

This PDF file includes:

  • Materials and Methods
  • Fig. S1. hiPSCs exhibit characteristic morphologies and markers of pluripotent stem cells.
  • Fig. S2. Quantitative and qualitative cell viability assays illustrate sorafenib, regorafenib, and ponatinib cytotoxicity in hiPSC-CMs.
  • Fig. S3. Quantitative cell viability assays on additional hiPSC-CM lines demonstrate VEGFR2/PDGFR-inhibiting TKI toxicity.
  • Fig. S4. Quantitative cell viability assays in hiPSC-CMs and hiPSC-ECs derived from patients receiving TKI treatment.
  • Fig. S5. Commercially available, healthy control hiPSC-CMs exhibit alterations in cellular contractility after a 72-hour TKI treatment.
  • Fig. S6. Heat maps of high-throughput contractility analysis on commercially available, healthy control hiPSC-CMs treated with TKIs.
  • Fig. S7. Extended calculations for TKI safety index after a 72-hour TKI treatment on commercially available, healthy control hiPSC-CMs.
  • Fig. S8. hiPSC-CMs exhibit alterations in cellular contractility after a 72-hour treatment with known QT interval–prolonging TKIs.
  • Fig. S9. hiPSC-ECs exhibit EC characteristics and demonstrate cytotoxicity in response to TKI treatment.
  • Fig. S10. hiPSC-CFs exhibit properties of adult cardiac fibroblasts and demonstrate cytotoxicity in response to TKI treatment.
  • Fig. S11. hiPSCs demonstrate a TKI cytotoxicity profile that is unique from those of hiPSC-CMs, hiPSC-ECs, and hiPSC-CFs.
  • Fig. S12. VEGFR2/PDGFR-inhibiting TKI treatment in hiPSC-CMs results in activation of compensatory insulin/IGF1 signaling.
  • Fig. S13. IGF1 and insulin treatment activates cardioprotective Akt signaling in hiPSC-CMs.
  • Fig. S14. IGF1 and insulin treatment rescues doxorubicin toxicity in hiPSC-CMs.
  • Fig. S15. IGF1 and insulin treatment rescues ponatinib toxicity at early time points in hiPSC-CMs.
  • Fig. S16. RNA-seq of hiPSC-CMs treated with the VEGFR2/PDGFR-inhibiting TKI sorafenib illustrates compensatory hyperactivation of VEGF signaling.
  • Table S1. Small-molecule TKIs selected for high-throughput cardiotoxicity screen.
  • Table S2. Adverse cardiac events associated with small-molecule TKIs selected for high-throughput cardiotoxicity screen.
  • Legend for movie S1
  • References (3250)

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Other Supplementary Material for this manuscript includes the following:

  • Movie S1 (.mp4 format). hiPSC-CMs before purification via glucose deprivation.