@article{4191,
  author = {Maedeh Mozneb and Amelia Jenkins and Samuel Sances and Stephany Pohlman and Michael J. Workman and Dylan West and Briana Ondatje and Kareem El-Ghazawi and Amanda Woodbury and Veronica J. Garcia and Shachi Patel and Madelyn Arzt and Felipe Dezem and Alex H. Laperle and V. Alexandra Moser and Ritchie Ho and Nur Yucer and Jasmine Plummer and Robert J. Barrett and Clive N. Svendsen and Arun Sharma},
  title = {Multi-lineage heart-chip models drug cardiotoxicity and enhances maturation of human stem cell-derived cardiovascular cells},
  abstract = {Cardiovascular toxicity causes adverse drug reactions and may lead to drug removal from the pharmaceutical market. Cancer therapies can induce life-threatening cardiovascular side effects such as arrhythmias, muscle cell death, or vascular dysfunction. New technologies have enabled cardiotoxic compounds to be identified earlier in drug development. Human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (CMs) and vascular endothelial cells (ECs) can screen for drug-induced alterations in cardiovascular cell function and survival. However, most existing hiPSC models for cardiovascular drug toxicity utilize two-dimensional, immature cells grown in static culture. Improved in vitro models to mechanistically interrogate cardiotoxicity would utilize more adult-like, mature hiPSC-derived cells in an integrated system whereby toxic drugs and protective agents can flow between hiPSC-ECs that represent systemic vasculature and hiPSC-CMs that represent heart muscle (myocardium). Such models would be useful for testing the multi-lineage cardiotoxicities of chemotherapeutic drugs such as VEGFR2/PDGFR-inhibiting tyrosine kinase inhibitors (VPTKIs). Here, we develop a multi-lineage, fully-integrated, cardiovascular organ-chip that can enhance hiPSC-EC and hiPSC-CM functional and genetic maturity, model endothelial barrier permeability, and demonstrate long-term functional stability. This microfluidic organ-chip harbors hiPSC-CMs and hiPSC-ECs on separate channels that can be subjected to active fluid flow and rhythmic biomechanical stretch. We demonstrate the utility of this cardiovascular organ-chip as a predictive platform for evaluating multi-lineage VPTKI toxicity. This study may lead to the development of new modalities for the evaluation and prevention of cancer therapy-induced cardiotoxicity.},
  year = {2024},
  journal = {Lab on a Chip},
  volume = {24},
  pages = {869-881},
  month = {2024-02-13},
  issn = {1473-0189},
  url = {https://pubs.rsc.org/en/content/articlelanding/2024/lc/d3lc00745f},
  doi = {10.1039/D3LC00745F},
  language = {en},
}