Optimization of the engineered 3D hepatic microenvironment enhances pluripotent stem cell derived hepatocyte

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Project summary In late 2019, COVID-19, a disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS- CoV-2) emerged in Wuhan, China and has rapidly impacted almost all countries around the world. Officially declared a global pandemic by the WHO, COVID-19 is a worldwide emergency and by million United with directly , current in vitro model platforms are so distinct from human infection that they may not capture key components of viral infection or virus-host interactions. May 29, 2020, over 5.8 COVID-19 cases were reported with over 360,000 deaths globally. Although originating in China the States has emerged as an epicenter of this pandemic with over 1.75 million COVID-19 cases reported over 103,000 deaths. Unfortunately there is no vaccine that can prevent SARS-CoV-2 infection or robust activing antivirals that can mitigate infection or alter disease progression. Moreover Given this local, national, and global emergency our near-term goal is on the development of novel and robust experimental cell culture models, virological tools, and to identify novel therapeutics for SARS-CoV-2 treatment. Our long-term goal is to elucidate the complex interactions and mechanisms underlying SARS-CoV-2 infection and host response. Given that our institution has been at the center of the COVID-19 pandemic here in the U.S. we have generated a wide database of clinical data that has revealed that a high prevalence of initial COVID- 19 presentations are with GI manifestations with over one-half of patients noted to have biochemical evidence of liver injury at presentation. The impact of SARS-CoV-2 infection on hepatocellular and cholangiocyte function remains unclear. To address these knowledge gaps we have generated several novel technologies and have assembled a robust team with complimentary expertise in stem cell biology, tissue engineering and virology, chemical screening and stem cell biology, and in virology/BSL3 expertise. We aim to identify drug candidates that impact SARS-CoV-2 viral infection while we evaluate host-virus interactions. Our work is urgently needed given the impacts SARS-CoV-2 has had on our local, national, and global communities and its potential impact on millions of people who already, or will in the future will develop COVID19 infection by shedding light on mechanisms, molecular targets, and potential drugs that could lead directly to the development of new antiviral treatments and therapies.