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Human Cardiac Ventricular‐Like Organoid Chambers and Tissue Strips From Pluripotent Stem Cells as a Two‐Tiered Assay for Inotropic Responses
Author(s) -
Keung Wendy,
Chan Patrick K.W.,
Backeris Peter C.,
Lee Eugene K.,
Wong Nicodemus,
Wong Andy O.T.,
Wong Gabriel K.Y.,
Chan Camie W.Y.,
Fermini Bernard,
Costa Kevin D.,
Li Ronald A.
Publication year - 2019
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1002/cpt.1385
Subject(s) - inotrope , organoid , false positive paradox , induced pluripotent stem cell , drug discovery , drug , pharmacology , stem cell , biology , assay sensitivity , medicine , computational biology , microbiology and biotechnology , pathology , bioinformatics , embryonic stem cell , computer science , genetics , gene , alternative medicine , machine learning
Traditional drug discovery is an inefficient process. Human pluripotent stem cell‐derived cardiomyocytes can potentially fill the gap between animal and clinical studies, but conventional two‐dimensional cultures inadequately recapitulate the human cardiac phenotype. Here, we systematically examined the pharmacological responses of engineered human ventricular‐like cardiac tissue strips (hv CTS ) and organoid chambers (hv COC ) to 25 cardioactive compounds covering various drug classes. While hv CTS effectively detected negative and null inotropic effects, the sensitivity to positive inotropes was modest. We further quantified the predictive capacity of hv CTS in a blinded screening, with accuracies for negative, positive, and null inotropic effects at 100%, 86%, and 80%, respectively. Interestingly, hv COC , with a pro‐maturation milieu that yields physiologically complex parameters, displayed enhanced positive inotropy. Based on these results, we propose a two‐tiered screening system for avoiding false positives and negatives. Such an approach would facilitate drug discovery by leading to better overall success.