Multi-Lineage Heart-Chip Models Drug Cardiotoxicity and Enhances Maturation of Human Stem Cell-Derived Cardiovascular Cells

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. Overall design: We've used the 02iCTR iPSC and gCaMP iPSC, and differentiated them into cardiomyocytes and endothelial cells, both used in a single channel of the Emulate chips. We've subjected both cell lines to flow and a cyclic mechanical stretch and the resultant cells are assessed for their gene distribution against static cultures. We've further tested the effect of a TKI drug Sorfenib on both cell types through the platform. The cells are human-derived iPSCs. We've used 4 replicates of iPSC-ECs and iPSC-CMs for RNA sequencing of the static conditions. 3 smaples of CMs under stretch and flow and 3 samples under flow only were tested for RNA-Seq as well. Finally we have tested 3 replicates of EC under flow and stretch and 2 replicate of ECs under flow only conditions, for RNA-Seq.