tetano
Editor, Senior Moderator
Cell Rep
. 2021 May 19;109218.
doi: 10.1016/j.celrep.2021.109218. Online ahead of print.
Direct derivation of human alveolospheres for SARS-CoV-2 infection modeling and drug screening
Toshiki Ebisudani[SUP] 1 [/SUP], Shinya Sugimoto[SUP] 2 [/SUP], Kei Haga[SUP] 3 [/SUP], Akifumi Mitsuishi[SUP] 1 [/SUP], Reiko Takai-Todaka[SUP] 3 [/SUP], Masayuki Fujii[SUP] 2 [/SUP], Kohta Toshimitsu[SUP] 2 [/SUP], Junko Hamamoto[SUP] 4 [/SUP], Kai Sugihara[SUP] 4 [/SUP], Tomoyuki Hishida[SUP] 5 [/SUP], Hisao Asamura[SUP] 5 [/SUP], Koichi Fukunaga[SUP] 6 [/SUP], Hiroyuki Yasuda[SUP] 7 [/SUP], Kazuhiko Katayama[SUP] 8 [/SUP], Toshiro Sato[SUP] 9 [/SUP]
Affiliations
Abstract
Although the main cellular target of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is thought to be alveolar cells, the absence of their tractable culture system precludes the development of a clinically relevant SARS-CoV-2 infection model. Here, we establish an efficient human alveolosphere culture method and sphere-based drug testing platform for SARS-CoV-2. Alveolospheres exhibit indolent growth in a Wnt- and R-spondin-dependent manner. Gene expression, immunofluorescence, and electron microscopy analyses reveal the presence of alveolar cells in alveolospheres. Alveolospheres express ACE2 and allow SARS-CoV-2 to propagate nearly 100,000-fold in 3 days of infection. Whereas lopinavir and nelfinavir, protease inhibitors used for the treatment of human immunodeficiency virus (HIV) infection, have a modest anti-viral effect on SARS-CoV-2, remdesivir, a nucleotide prodrug, shows an anti-viral effect at the concentration comparable with the circulating drug level. These results demonstrate the validity of the alveolosphere culture system for the development of therapeutic agents to combat SARS-CoV-2.
Keywords: COVID-19; alveolosphere; drug screening; lung; organoid; stem cell niche.
. 2021 May 19;109218.
doi: 10.1016/j.celrep.2021.109218. Online ahead of print.
Direct derivation of human alveolospheres for SARS-CoV-2 infection modeling and drug screening
Toshiki Ebisudani[SUP] 1 [/SUP], Shinya Sugimoto[SUP] 2 [/SUP], Kei Haga[SUP] 3 [/SUP], Akifumi Mitsuishi[SUP] 1 [/SUP], Reiko Takai-Todaka[SUP] 3 [/SUP], Masayuki Fujii[SUP] 2 [/SUP], Kohta Toshimitsu[SUP] 2 [/SUP], Junko Hamamoto[SUP] 4 [/SUP], Kai Sugihara[SUP] 4 [/SUP], Tomoyuki Hishida[SUP] 5 [/SUP], Hisao Asamura[SUP] 5 [/SUP], Koichi Fukunaga[SUP] 6 [/SUP], Hiroyuki Yasuda[SUP] 7 [/SUP], Kazuhiko Katayama[SUP] 8 [/SUP], Toshiro Sato[SUP] 9 [/SUP]
Affiliations
- PMID: 34038715
- DOI: 10.1016/j.celrep.2021.109218
Abstract
Although the main cellular target of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is thought to be alveolar cells, the absence of their tractable culture system precludes the development of a clinically relevant SARS-CoV-2 infection model. Here, we establish an efficient human alveolosphere culture method and sphere-based drug testing platform for SARS-CoV-2. Alveolospheres exhibit indolent growth in a Wnt- and R-spondin-dependent manner. Gene expression, immunofluorescence, and electron microscopy analyses reveal the presence of alveolar cells in alveolospheres. Alveolospheres express ACE2 and allow SARS-CoV-2 to propagate nearly 100,000-fold in 3 days of infection. Whereas lopinavir and nelfinavir, protease inhibitors used for the treatment of human immunodeficiency virus (HIV) infection, have a modest anti-viral effect on SARS-CoV-2, remdesivir, a nucleotide prodrug, shows an anti-viral effect at the concentration comparable with the circulating drug level. These results demonstrate the validity of the alveolosphere culture system for the development of therapeutic agents to combat SARS-CoV-2.
Keywords: COVID-19; alveolosphere; drug screening; lung; organoid; stem cell niche.