Multi-lineage heart-chip models drug cardiotoxicity and enhances maturation of human stem cell-derived cardiovascular cells
Maedeh Mozneb, Amelia Jenkins, Samuel Sances, Stephany Pohlman, Michael J. Workman, Dylan West, Briana Ondatje, Kareem El-Ghazawi, Amanda Woodbury, Veronica J. Garcia, Shachi Patel, Madelyn Arzt, Felipe Segato Dezem, Alex Laperle, V. Alexandra Moser, Ritchie Ho, Nur Yucer, Jasmine Plummer, Robert J. Barrett, Clive N. Svendsen, Arun Sharma
Abstract
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.