TY - JOUR
T1 - A bipotential organoid model of respiratory epithelium recapitulates high infectivity of SARS-CoV-2 Omicron variant
AU - Chiu, Man Chun
AU - Li, Cun
AU - Liu, Xiaojuan
AU - Yu, Yifei
AU - Huang, Jingjing
AU - Wan, Zhixin
AU - Xiao, Ding
AU - Chu, Hin
AU - Cai, Jian Piao
AU - Zhou, Biao
AU - Sit, Ko Yung
AU - Au, Wing Kuk
AU - Wong, Kenneth Kak Yuen
AU - Li, Gang
AU - Chan, Jasper Fuk Woo
AU - To, Kelvin Kai Wang
AU - Chen, Zhiwei
AU - Jiang, Shibo
AU - Clevers, Hans
AU - Yuen, Kwok Yung
AU - Zhou, Jie
N1 - Funding Information:
We thank the Center of PanorOmic Sciences and Electron Microscope Unit, Li Ka Shing Faculty of Medicine, The University of Hong Kong, for assistance in confocal imaging, flow cytometry, and electron microscopy. This work was partly supported by funding from the Health and Medical Research Fund (HMRF, 17161272 and 19180392) of the Food and Health Bureau of the HKSAR government to J.Z.; General Research Fund (GRF, 17105420) and Collaborative Research Fund (CRF, C7042-21G) of the Research Grants Council of HKSAR government to J.Z.; Health@InnoHK, Innovation and Technology Commission, HKSAR Government to K.Y.Y.; and the donations of Hong Kong Sanatorium and Hospital, the Shaw Foundation Hong Kong, May Tam Mak Mei Yin, Richard Yu and Carol Yu, Lee Wan Keung Charity Foundation Limited, Hui Ming, Hui Hoy and Chow Sin Lan Charity Fund Limited, Chan Yin Chuen Memorial Charitable Foundation, Perfect Shape Medical Limited, Kai Chong Tong, Foo Oi Foundation Limited to K.Y.Y.
Funding Information:
J.Z. designed the experiments. M.C.C., C.L., X.L., Y.Y., J.H., Z.W., and D.X. performed the experiments. J.Z., M.C.C., C.L., X.L., and Hin C. analyzed and interpreted the data. J.-P.C., B.Z., G.L., and Z.C. contributed the antibodies. K.-Y.S., W.-K.A., K.K.-Y.W., J.F.-W.C., and K.K.W.T. provided human tissues. S.J., Hans C., and K.Y.Y. provided conceptual advice. J.Z. and K.Y.Y. provided financial support. J.Z., S.J., Hans. C., and K.Y.Y. wrote the manuscript.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/6/17
Y1 - 2022/6/17
N2 - The airways and alveoli of the human respiratory tract are lined by two distinct types of epithelium, which are the primary targets of respiratory viruses. We previously established long-term expanding human lung epithelial organoids from lung tissues and developed a ‘proximal’ differentiation protocol to generate mucociliary airway organoids. However, a respiratory organoid system with bipotential of the airway and alveolar differentiation remains elusive. Here we defined a ‘distal’ differentiation approach to generate alveolar organoids from the same source for the derivation of airway organoids. The alveolar organoids consisting of type I and type II alveolar epithelial cells (AT1 and AT2, respectively) functionally simulate the alveolar epithelium. AT2 cells maintained in lung organoids serve as progenitor cells from which alveolar organoids derive. Moreover, alveolar organoids sustain a productive SARS-CoV-2 infection, albeit a lower replicative fitness was observed compared to that in airway organoids. We further optimized 2-dimensional (2D) airway organoids. Upon differentiation under a slightly acidic pH, the 2D airway organoids exhibit enhanced viral replication, representing an optimal in vitro correlate of respiratory epithelium for modeling the high infectivity of SARS-CoV-2. Notably, the higher infectivity and replicative fitness of the Omicron variant than an ancestral strain were accurately recapitulated in these optimized airway organoids. In conclusion, we have established a bipotential organoid culture system able to reproducibly expand the entire human respiratory epithelium in vitro for modeling respiratory diseases, including COVID-19.
AB - The airways and alveoli of the human respiratory tract are lined by two distinct types of epithelium, which are the primary targets of respiratory viruses. We previously established long-term expanding human lung epithelial organoids from lung tissues and developed a ‘proximal’ differentiation protocol to generate mucociliary airway organoids. However, a respiratory organoid system with bipotential of the airway and alveolar differentiation remains elusive. Here we defined a ‘distal’ differentiation approach to generate alveolar organoids from the same source for the derivation of airway organoids. The alveolar organoids consisting of type I and type II alveolar epithelial cells (AT1 and AT2, respectively) functionally simulate the alveolar epithelium. AT2 cells maintained in lung organoids serve as progenitor cells from which alveolar organoids derive. Moreover, alveolar organoids sustain a productive SARS-CoV-2 infection, albeit a lower replicative fitness was observed compared to that in airway organoids. We further optimized 2-dimensional (2D) airway organoids. Upon differentiation under a slightly acidic pH, the 2D airway organoids exhibit enhanced viral replication, representing an optimal in vitro correlate of respiratory epithelium for modeling the high infectivity of SARS-CoV-2. Notably, the higher infectivity and replicative fitness of the Omicron variant than an ancestral strain were accurately recapitulated in these optimized airway organoids. In conclusion, we have established a bipotential organoid culture system able to reproducibly expand the entire human respiratory epithelium in vitro for modeling respiratory diseases, including COVID-19.
UR - http://www.scopus.com/inward/record.url?scp=85132165291&partnerID=8YFLogxK
U2 - 10.1038/s41421-022-00422-1
DO - 10.1038/s41421-022-00422-1
M3 - Article
C2 - 35710786
AN - SCOPUS:85132165291
SN - 2056-5968
VL - 8
JO - Cell Discovery
JF - Cell Discovery
IS - 1
M1 - 57
ER -