Human Pluripotent Stem Cell-Derived Neural Cells and Brain Organoids Reveal SARS-CoV-2 Neurotropism Predominates in Choroid Plexus Epithelium

Fadi Jacob; Sarshan R Pather; Wei-Kai Huang; Feng Zhang; Samuel Zheng Hao Wong; Haowen Zhou; Beatrice Cubitt; Wenqiang Fan; Catherine Z Chen; Miao Xu; Manisha Pradhan; Daniel Y Zhang; Wei Zheng; Anne G Bang; Hongjun Song; Juan Carlos de la Torre; Guo-Li Ming

doi:10.1016/j.stem.2020.09.016

Human Pluripotent Stem Cell-Derived Neural Cells and Brain Organoids Reveal SARS-CoV-2 Neurotropism Predominates in Choroid Plexus Epithelium

Cell Stem Cell. 2020 Dec 3;27(6):937-950.e9. doi: 10.1016/j.stem.2020.09.016. Epub 2020 Sep 21.

Authors

Fadi Jacob¹, Sarshan R Pather², Wei-Kai Huang³, Feng Zhang⁴, Samuel Zheng Hao Wong⁵, Haowen Zhou⁶, Beatrice Cubitt⁷, Wenqiang Fan⁴, Catherine Z Chen⁸, Miao Xu⁸, Manisha Pradhan⁸, Daniel Y Zhang⁹, Wei Zheng⁸, Anne G Bang¹⁰, Hongjun Song¹¹, Juan Carlos de la Torre¹², Guo-Li Ming¹³

Affiliations

¹ Department of Neuroscience and Mahoney Institute for Neurosciences, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Medical Scientist Training Program, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
² Cell and Molecular Biology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
³ Department of Neuroscience and Mahoney Institute for Neurosciences, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Graduate Program in Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁴ Department of Neuroscience and Mahoney Institute for Neurosciences, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁵ Department of Neuroscience and Mahoney Institute for Neurosciences, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Graduate Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁶ Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
⁷ Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA.
⁸ National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Bethesda, MD 20892, USA.
⁹ Biochemistry and Molecular Biophysics Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
¹⁰ Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA. Electronic address: abang@sbpdiscovery.org.
¹¹ Department of Neuroscience and Mahoney Institute for Neurosciences, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Regenerative Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; The Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: shongjun@pennmedicine.upenn.edu.
¹² Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA. Electronic address: juanct@scripps.edu.
¹³ Department of Neuroscience and Mahoney Institute for Neurosciences, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Regenerative Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: gming@pennmedicine.upenn.edu.

Abstract

Neurological complications are common in patients with COVID-19. Although severe acute respiratory syndrome coronavirus 2 (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 is not well understood. 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 that neurons and astrocytes were sparsely infected, but choroid plexus epithelial cells underwent robust infection. We optimized a protocol to generate choroid plexus organoids from hiPSCs and showed that productive SARS-CoV-2 infection of these organoids is associated with increased cell death and transcriptional dysregulation indicative of an inflammatory response and cellular function deficits. Together, our findings provide evidence for selective SARS-CoV-2 neurotropism and support the use of hiPSC-derived brain organoids as a platform to investigate SARS-CoV-2 infection susceptibility of brain cells, mechanisms of virus-induced brain dysfunction, and treatment strategies.

Keywords: COVID-19; SARS-CoV-2; astrocyte; brain organoid; choroid plexus organoid; cortical organoid; hippocampal organoid; human iPSCs; hypothalamic organoid; midbrain organoid; neuron; neurotropism.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Astrocytes / virology
Brain / cytology
Brain / virology
COVID-19 / genetics
COVID-19 / virology
Cells, Cultured
Choroid Plexus / virology*
Gene Expression Regulation
Humans
Neural Stem Cells / virology*
Neurons / virology
Organoids / virology*
Pluripotent Stem Cells / virology*
SARS-CoV-2 / physiology*
Viral Tropism*

Abstract

Publication types

MeSH terms

Grants and funding