A Human Pluripotent Stem Cell Approach to COVID-19 (Invited Speaker)

There is an urgent need to create novel models using human disease-relevant cells to study SARS-CoV-2 biology and to facilitate development of therapy. As SARS-CoV-2 primarily infects the respiratory tract, we developed a lung organoid model using human pluripotent stem cells (hPSC-LOs). The hPSC-LOs, particularly alveolar type II-like cells, are permissive to SARS-CoV-2 infection, and showed robust induction of chemokines upon SARS-CoV-2 infection, similar to what is seen in COVID-19 patients. Using hPSC-LOs, we performed a high throughput screen of FDA-approved drugs and identified entry inhibitors of SARS-CoV-2. Besides human lung models of COVID-19, we used directed differentiation of hPSC to establish a lung and macrophage co-culture system and model the host-pathogen interaction and immune response caused by SARS-CoV-2 infection. Our studies reveal differential immune response patterns in distinct macrophage phenotypes, which could be contributing factors to the spectrum of COVID-19 severity. Together, these data demonstrate that hPSC-cells infected by SARS-CoV-2 can serve as disease models to study SARS-CoV-2 infection and provide a valuable resource for developing COVID-19 therapeutics.