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Modeling COVID-19 with Human Pluripotent Stem Cell-Derived Cells Reveals Synergistic Effects of Anti-inflammatory Macrophages with ACE2 Inhibition Against SARS-CoV-2

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 unders...

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Autores principales: Duan, Fuyu, Guo, Liyan, Yang, Liuliu, Han, Yuling, Thakur, Abhimanyu, Nilsson-Payant, Benjamin E., Wang, Pengfei, Zhang, Zhao, Yan Ma, Chui, Zhou, Xiaoya, Han, Teng, Zhang, Tuo, Wang, Xing, Xu, Dong, Duan, Xiaohua, Xiang, Jenny, Tse, Hung-fat, Liao, Can, Luo, Weiren, Huang, Fang-Ping, Chen, Ya-Wen, Evans, Todd, Schwartz, Robert E., tenOever, Benjamin, Ho, David D., Chen, Shuibing, Na, Jie, Lian, Qizhou, Chen, Huanhuan Joyce
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Journal Experts 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7444287/
https://www.ncbi.nlm.nih.gov/pubmed/32839764
http://dx.doi.org/10.21203/rs.3.rs-62758/v2
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author Duan, Fuyu
Guo, Liyan
Yang, Liuliu
Han, Yuling
Thakur, Abhimanyu
Nilsson-Payant, Benjamin E.
Wang, Pengfei
Zhang, Zhao
Yan Ma, Chui
Zhou, Xiaoya
Han, Teng
Zhang, Tuo
Wang, Xing
Xu, Dong
Duan, Xiaohua
Xiang, Jenny
Tse, Hung-fat
Liao, Can
Luo, Weiren
Huang, Fang-Ping
Chen, Ya-Wen
Evans, Todd
Schwartz, Robert E.
tenOever, Benjamin
Ho, David D.
Chen, Shuibing
Na, Jie
Lian, Qizhou
Chen, Huanhuan Joyce
author_facet Duan, Fuyu
Guo, Liyan
Yang, Liuliu
Han, Yuling
Thakur, Abhimanyu
Nilsson-Payant, Benjamin E.
Wang, Pengfei
Zhang, Zhao
Yan Ma, Chui
Zhou, Xiaoya
Han, Teng
Zhang, Tuo
Wang, Xing
Xu, Dong
Duan, Xiaohua
Xiang, Jenny
Tse, Hung-fat
Liao, Can
Luo, Weiren
Huang, Fang-Ping
Chen, Ya-Wen
Evans, Todd
Schwartz, Robert E.
tenOever, Benjamin
Ho, David D.
Chen, Shuibing
Na, Jie
Lian, Qizhou
Chen, Huanhuan Joyce
author_sort Duan, Fuyu
collection PubMed
description 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.
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spelling pubmed-74442872020-08-25 Modeling COVID-19 with Human Pluripotent Stem Cell-Derived Cells Reveals Synergistic Effects of Anti-inflammatory Macrophages with ACE2 Inhibition Against SARS-CoV-2 Duan, Fuyu Guo, Liyan Yang, Liuliu Han, Yuling Thakur, Abhimanyu Nilsson-Payant, Benjamin E. Wang, Pengfei Zhang, Zhao Yan Ma, Chui Zhou, Xiaoya Han, Teng Zhang, Tuo Wang, Xing Xu, Dong Duan, Xiaohua Xiang, Jenny Tse, Hung-fat Liao, Can Luo, Weiren Huang, Fang-Ping Chen, Ya-Wen Evans, Todd Schwartz, Robert E. tenOever, Benjamin Ho, David D. Chen, Shuibing Na, Jie Lian, Qizhou Chen, Huanhuan Joyce Res Sq Article 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. American Journal Experts 2020-09-15 /pmc/articles/PMC7444287/ /pubmed/32839764 http://dx.doi.org/10.21203/rs.3.rs-62758/v2 Text en https://creativecommons.org/licenses/by/4.0/This work is licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/) , which allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use.
spellingShingle Article
Duan, Fuyu
Guo, Liyan
Yang, Liuliu
Han, Yuling
Thakur, Abhimanyu
Nilsson-Payant, Benjamin E.
Wang, Pengfei
Zhang, Zhao
Yan Ma, Chui
Zhou, Xiaoya
Han, Teng
Zhang, Tuo
Wang, Xing
Xu, Dong
Duan, Xiaohua
Xiang, Jenny
Tse, Hung-fat
Liao, Can
Luo, Weiren
Huang, Fang-Ping
Chen, Ya-Wen
Evans, Todd
Schwartz, Robert E.
tenOever, Benjamin
Ho, David D.
Chen, Shuibing
Na, Jie
Lian, Qizhou
Chen, Huanhuan Joyce
Modeling COVID-19 with Human Pluripotent Stem Cell-Derived Cells Reveals Synergistic Effects of Anti-inflammatory Macrophages with ACE2 Inhibition Against SARS-CoV-2
title Modeling COVID-19 with Human Pluripotent Stem Cell-Derived Cells Reveals Synergistic Effects of Anti-inflammatory Macrophages with ACE2 Inhibition Against SARS-CoV-2
title_full Modeling COVID-19 with Human Pluripotent Stem Cell-Derived Cells Reveals Synergistic Effects of Anti-inflammatory Macrophages with ACE2 Inhibition Against SARS-CoV-2
title_fullStr Modeling COVID-19 with Human Pluripotent Stem Cell-Derived Cells Reveals Synergistic Effects of Anti-inflammatory Macrophages with ACE2 Inhibition Against SARS-CoV-2
title_full_unstemmed Modeling COVID-19 with Human Pluripotent Stem Cell-Derived Cells Reveals Synergistic Effects of Anti-inflammatory Macrophages with ACE2 Inhibition Against SARS-CoV-2
title_short Modeling COVID-19 with Human Pluripotent Stem Cell-Derived Cells Reveals Synergistic Effects of Anti-inflammatory Macrophages with ACE2 Inhibition Against SARS-CoV-2
title_sort modeling covid-19 with human pluripotent stem cell-derived cells reveals synergistic effects of anti-inflammatory macrophages with ace2 inhibition against sars-cov-2
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7444287/
https://www.ncbi.nlm.nih.gov/pubmed/32839764
http://dx.doi.org/10.21203/rs.3.rs-62758/v2
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