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Human Pluripotent Stem Cell-Derived Neural Cells and Brain Organoids Reveal SARS-CoV-2 Neurotropism

View ORCID ProfileFadi Jacob, Sarshan R. Pather, Wei-Kai Huang, Samuel Zheng Hao Wong, Haowen Zhou, Feng Zhang, Beatrice Cubitt, Catherine Z. Chen, Miao Xu, Manisha Pradhan, Daniel Y. Zhang, Wei Zheng, Anne G. Bang, Hongjun Song, Juan Carlos de a Torre, Guo-li Ming
doi: https://doi.org/10.1101/2020.07.28.225151
Fadi Jacob
1Department of Neuroscience and Mahoney Institute for Neurosciences, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
2The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
3Medical Scientist Training Program, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
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  • ORCID record for Fadi Jacob
Sarshan R. Pather
4Cell and Molecular Biology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
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Wei-Kai Huang
1Department of Neuroscience and Mahoney Institute for Neurosciences, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
5Graduate Program in Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
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Samuel Zheng Hao Wong
1Department of Neuroscience and Mahoney Institute for Neurosciences, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
6Graduate Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
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Haowen Zhou
7Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA
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Feng Zhang
1Department of Neuroscience and Mahoney Institute for Neurosciences, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
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Beatrice Cubitt
8Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA
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Catherine Z. Chen
9National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Bethesda, MD 20892, USA
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Miao Xu
9National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Bethesda, MD 20892, USA
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Manisha Pradhan
9National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Bethesda, MD 20892, USA
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Daniel Y. Zhang
10Biochemistry and Molecular Biophysics Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
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Wei Zheng
9National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Bethesda, MD 20892, USA
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Anne G. Bang
7Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA
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  • For correspondence: abang@sbpdiscovery.org shongjun@pennmedicine.upenn.edu juanct@scripps.edu gming@pennmedicine.upenn.edu
Hongjun Song
1Department of Neuroscience and Mahoney Institute for Neurosciences, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
11Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
12Institute for Regenerative Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
13The Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
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  • For correspondence: abang@sbpdiscovery.org shongjun@pennmedicine.upenn.edu juanct@scripps.edu gming@pennmedicine.upenn.edu
Juan Carlos de a Torre
8Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA
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  • For correspondence: abang@sbpdiscovery.org shongjun@pennmedicine.upenn.edu juanct@scripps.edu gming@pennmedicine.upenn.edu
Guo-li Ming
1Department of Neuroscience and Mahoney Institute for Neurosciences, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
11Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
12Institute for Regenerative Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
14Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
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  • For correspondence: abang@sbpdiscovery.org shongjun@pennmedicine.upenn.edu juanct@scripps.edu gming@pennmedicine.upenn.edu
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SUMMARY

Neurological complications are common in patients with COVID-19. While SARS-CoV-2, the causal pathogen of COVID-19, has been detected in some patient brains, its ability to infect brain cells and impact their function are not well understood, and experimental models using human brain cells are urgently needed. Here we investigated the susceptibility of human induced pluripotent stem cell (hiPSC)-derived monolayer brain cells and region-specific brain organoids to SARS-CoV-2 infection. We found modest numbers of infected neurons and astrocytes, but greater infection of choroid plexus epithelial cells. We optimized a protocol to generate choroid plexus organoids from hiPSCs, which revealed productive SARS-CoV-2 infection that leads to increased cell death and transcriptional dysregulation indicative of an inflammatory response and cellular function deficits. Together, our results provide evidence for SARS-CoV-2 neurotropism and support use of hiPSC-derived brain organoids as a platform to investigate the cellular susceptibility, disease mechanisms, and treatment strategies for SARS-CoV-2 infection.

Competing Interest Statement

The authors have declared no competing interest.

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Posted July 28, 2020.
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Human Pluripotent Stem Cell-Derived Neural Cells and Brain Organoids Reveal SARS-CoV-2 Neurotropism
Fadi Jacob, Sarshan R. Pather, Wei-Kai Huang, Samuel Zheng Hao Wong, Haowen Zhou, Feng Zhang, Beatrice Cubitt, Catherine Z. Chen, Miao Xu, Manisha Pradhan, Daniel Y. Zhang, Wei Zheng, Anne G. Bang, Hongjun Song, Juan Carlos de a Torre, Guo-li Ming
bioRxiv 2020.07.28.225151; doi: https://doi.org/10.1101/2020.07.28.225151
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Human Pluripotent Stem Cell-Derived Neural Cells and Brain Organoids Reveal SARS-CoV-2 Neurotropism
Fadi Jacob, Sarshan R. Pather, Wei-Kai Huang, Samuel Zheng Hao Wong, Haowen Zhou, Feng Zhang, Beatrice Cubitt, Catherine Z. Chen, Miao Xu, Manisha Pradhan, Daniel Y. Zhang, Wei Zheng, Anne G. Bang, Hongjun Song, Juan Carlos de a Torre, Guo-li Ming
bioRxiv 2020.07.28.225151; doi: https://doi.org/10.1101/2020.07.28.225151

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