Modeling COVID-19 with Human Pluripotent Stem Cell-Derived Cells Reveals Synergistic Effects of Anti-inflammatory Macrophages with ACE2 Inhibition Against SARS-CoV-2.
Fuyu Duan, Liyan Guo, Liuliu Yang, Yuling Han, Abhimanyu Thakur, Benjamin E Nilsson-Payant, Pengfei Wang, Zhao Zhang, Chui Yan Ma, Xiaoya Zhou, Teng Han, Tuo Zhang, Xing Wang, Dong Xu, Xiaohua Duan, Jenny Xiang, Hung-Fat Tse, Can Liao, Weiren Luo, Fang-Ping Huang, Ya-Wen Chen, Todd Evans, Robert E Schwartz, Benjamin tenOever, David D Ho, Shuibing Chen, Jie Na, Qizhou Lian, Huanhuan Joyce Chen
Author Information
Fuyu Duan: School of Medicine, Tsinghua University.
Liyan Guo: Prenatal Diagnostic Centre and Cord Blood Bank, Guangzhou Women and Children's Medical Center, Guangzhou Medical University.
Liuliu Yang: Department of Surgery, Weill Cornell Medicine.
Yuling Han: Department of Surgery, Weill Cornell Medicine.
Abhimanyu Thakur: The Pritzker School of Molecular Engineering, the University of Chicago.
Benjamin E Nilsson-Payant: Department of Microbiology, Icahn School of Medicine at Mount Sinai.
Pengfei Wang: Aaron Diamond AIDS Research Center, Columbia University Irving Medical Center.
Zhao Zhang: Department of Medicine, Li Ka Shing Faculty of Medicine; the University of Hong Kong.
Chui Yan Ma: Department of Medicine, Li Ka Shing Faculty of Medicine; the University of Hong Kong.
Xiaoya Zhou: Prenatal Diagnostic Centre and Cord Blood Bank, Guangzhou Women and Children's Medical Cent.
Teng Han: Sandra and Edward Meyer Cancer Center, Department of Medicine, Weill Cornell Medicine.
Tuo Zhang: Genomic Resource Core Facility, Weill Cornell Medicine.
Dysfunctional immune responses contribute critically to the progression of Coronavirus Disease-2019 (COVID-19) from mild to severe stages including fatality, with pro-inflammatory macrophages as one of the main mediators of lung hyper-inflammation. Therefore, there is an urgent need to better understand the interactions among SARS-CoV-2 permissive cells, macrophage, and the SARS-CoV-2 virus, thereby offering important insights into new therapeutic strategies. Here, we used directed differentiation of human pluripotent stem cells (hPSCs) to establish a lung and macrophage co-culture system and model the host-pathogen interaction and immune response caused by SARS-CoV-2 infection. Among the hPSC-derived lung cells, alveolar type II and ciliated cells are the major cell populations expressing the viral receptor ACE2 and co-effector TMPRSS2, and both were highly permissive to viral infection. We found that alternatively polarized macrophages (M2) and classically polarized macrophages (M1) had similar inhibitory effects on SARS-CoV-2 infection. However, only M1 macrophages significantly up-regulated inflammatory factors including IL-6 and IL-18, inhibiting growth and enhancing apoptosis of lung cells. Inhibiting viral entry into target cells using an ACE2 blocking antibody enhanced the activity of M2 macrophages, resulting in nearly complete clearance of virus and protection of lung cells. These results suggest a potential therapeutic strategy, in that by blocking viral entrance to target cells while boosting anti-inflammatory action of macrophages at an early stage of infection, M2 macrophages can eliminate SARS-CoV-2, while sparing lung cells and suppressing the dysfunctional hyper-inflammatory response mediated by M1 macrophages.
