A Human Pluripotent Stem Cell-based Platform to Study SARS-CoV-2 Tropism and Model Virus Infection in Human Cells and Organoids

Yang, Liuliu; Han, Yuling; Nilsson-Payant, Benjamin E.; Gupta, Vikas; Wang, Pengfei; Duan, Xiaohua; Tang, Xuming; Zhu, Jiajun; Zhao, Zeping; Jaffré, Fabrice; Zhang, Tuo; Kim, Tae Wan; Harschnitz, Oliver; Redmond, David; Houghton, Sean; Liu, Chengyang; Naji, Ali; Ciceri, Gabriele; Guttikonda, Sudha; Bram, Yaron; Nguyen, Duc-Huy T.; Cioffi, Michele; Chandar, Vasuretha; Hoagland, Daisy A.; Huang, Yaoxing; Xiang, Jenny; Wang, Hui; Lyden, David; Borczuk, Alain; Chen, Huanhuan Joyce; Studer, Lorenz; Pan, Fong Cheng; Ho, David D.; tenOever, Benjamin R.; Evans, Todd; Schwartz, Robert E.; Chen, Shuibing

SARS-CoV-2 has caused the COVID-19 pandemic. There is an urgent need for physiological models to study SARS-CoV-2 infection using human disease-relevant cells. COVID-19 pathophysiology includes respiratory failure but involves other organ systems including gut, liver, heart, and pancreas. We present an experimental platform comprised of cell and organoid derivatives from human pluripotent stem cells (hPSCs). A Spike-enabled pseudo-entry virus infects pancreatic endocrine cells, liver organoids, cardiomyocytes, and dopaminergic neurons. Recent clinical studies show a strong association with COVID-19 and diabetes. We find that human pancreatic beta cells and liver organoids are highly permissive to SARS-CoV-2 infection, further validated using adult primary human islets and adult hepatocyte and cholangiocyte organoids. SARS-CoV-2 infection caused striking expression of chemokines, as also seen in primary human COVID-19 pulmonary autopsy samples. hPSC-derived cells/organoids provide valuable models for understanding the cellular responses of human tissues to SARS-CoV-2 infection and for disease modeling of COVID-19.