Drug development is hampered by high failure rates attributed to the reliance on non-human animal models employed during safety and efficacy testing. A fundamental problem in this inefficient process is that non- human animal models neither adequately represent human biology nor recapitulate human disease states. The discovery of patient-specific human induced pluripotent stem (hiPS) cells creates the opportunity to develop in vitro disease-specific model tissues to be used for high content drug screening and patient specific medicine. The principal milestone of this proposal is to establish integrated in vitro models of human cardiac and liver tissue based on microphysiological models of human myocardium and liver with populations of normal and patient-specific hiPS cells differentiated into cardiomyocytes or hepatocytes. We chose the heart and liver as model systems, since failure of candidate drugs is most often associated with toxicity of one of these organs. For this UH2 application we have chosen to focus on long QT syndrome as a basis for proof-of-principle of our methodology. Prolongation of the QT interval, the electrical manifestation of cardiac ventricular repolarization, is a major cause of cardiac arrhythmias and sudden death. Our model will allow for controlled fabrication of human cardiac tissue to study the function of healthy and diseased within novel microfluidic systems. We plan to integrate the diseased cardiac tissue model with a "healthy" liver model on a microfluidic platform, and then use this device as proof-of-principle system to screen drugs to "treat" the LQTS. As the heart and liver models will be integrated, we can screen for both direct and off-target toxicity of drugs on the liver. At the end of the UH2 phase, we anticipate our platform will be easily adaptable to design changes and able to integrate with other physiological systems developed by competing groups during the UH3 phase.
The principal milestone of this proposal is to establish integrated in vitro models of human cardiac and liver tissue based on microphysiological models of human myocardium and liver with populations of normal and patient-specific human induced pluripotent stem (iPS) cells differentiated into cardiomyocytes or hepatocytes. This microphysiological system represents a significant advancement for understanding, studying, and developing new strategies for treating cardiovascular disease, such as long QT syndrome, a fatal disease. This project will focus on formation of cardiac and liver tissues, within a microfluidic platform, that can be widely used by the research community.
|Mathur, Anurag; Ma, Zhen; Loskill, Peter et al. (2016) In vitro cardiac tissue models: Current status and future prospects. Adv Drug Deliv Rev 96:203-13|
|Huebsch, Nathaniel; Loskill, Peter; Deveshwar, Nikhil et al. (2016) Miniaturized iPS-Cell-Derived Cardiac Muscles for Physiologically Relevant Drug Response Analyses. Sci Rep 6:24726|
|Ma, Zhen; Wang, Jason; Loskill, Peter et al. (2015) Self-organizing human cardiac microchambers mediated by geometric confinement. Nat Commun 6:7413|
|Huebsch, Nathaniel; Loskill, Peter; Mandegar, Mohammad A et al. (2015) Automated Video-Based Analysis of Contractility and Calcium Flux in Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes Cultured over Different Spatial Scales. Tissue Eng Part C Methods 21:467-79|
|Mathur, Anurag; Loskill, Peter; Shao, Kaifeng et al. (2015) Human iPSC-based cardiac microphysiological system for drug screening applications. Sci Rep 5:8883|
|Ma, Zhen; Koo, Sangmo; Finnegan, Micaela A et al. (2014) Three-dimensional filamentous human diseased cardiac tissue model. Biomaterials 35:1367-77|
|Spencer, C Ian; Baba, Shiro; Nakamura, Kenta et al. (2014) Calcium transients closely reflect prolonged action potentials in iPSC models of inherited cardiac arrhythmia. Stem Cell Reports 3:269-81|
|Yum, Kyungsuk; Hong, Soon Gweon; Healy, Kevin E et al. (2014) Physiologically relevant organs on chips. Biotechnol J 9:16-27|
|Zhu, Saiyong; Rezvani, Milad; Harbell, Jack et al. (2014) Mouse liver repopulation with hepatocytes generated from human fibroblasts. Nature 508:93-7|
|Mathur, Anurag; Loskill, Peter; Hong, Soongweon et al. (2013) Human induced pluripotent stem cell-based microphysiological tissue models of myocardium and liver for drug development. Stem Cell Res Ther 4 Suppl 1:S14|
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