Self-Organizing, Symmetry Breaking, Isogenic Human Lung Buds on Microchips Identify Alveolar Stem Cells as Novel Targets of SARS-CoV-2

Abstract

Although lung disease is the primary clinical outcome in COVID-19 patients, how SARS-CoV-2 induces lung pathology remains elusive. Here we describe a high-throughput platform to generate self-organizing, nearly identical, and genetically-matched human lung buds derived from hESCs cultured on micropatterned substrates. Synthetic lung buds resemble human fetal lungs and display proximo-distal patterning of alveolar and airway tissue directed by KGF. They are susceptible to infection by SARS-CoV-2 and endemic coronaviruses and can be used to track cell type-specific cytopathic effects in hundreds of lung buds in parallel. We detected an increased susceptibility to infection in alveolar cells and identified cycling alveolar stem cells as new targets of SARS-CoV-2. We used this platform to test neutralizing antibodies that efficiently blocked SARS-CoV-2 infection and transmission. Synthetic lung buds offer unlimited, rapid and scalable access to disease-relevant tissue that recapitulates human lung morphogenesis to identify key vulnerabilities for COVID-19 and respiratory viruses.Funding: This work was supported by the Pershing Square Foundation, NIH grants P01AI138398-S1, 2U19AI111825, and R01AI091707-10S1, a George Mason University Fast Grant, the BAWD Foundation, the G. Harold and Leila Y. Mathers Charitable Foundation, and private funding from the Rockefeller University.Conflict of Interest: A.H.B. is a co-founder of 2 startup companies: Rumi Scientific Inc. and OvaNova Laboratories, LLC and serves on their scientific advisory boards. C.M.R. is a founder of Apath LLC, a Scientific Advisory Board member of Imvaq Therapeutics, Vir Biotechnology, and Arbutus Biopharma, and an advisor for Regulus Therapeutics and Pfizer. All other authors declare no competing interests.