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Adult stem cell-derived complete lung organoid models emulate lung disease in COVID-19
BACKGROUND: SARS-CoV-2, the virus responsible for COVID-19, causes widespread damage in the lungs in the setting of an overzealous immune response whose origin remains unclear. METHODS: We present a scalable, propagable, personalized, cost-effective adult stem cell-derived human lung organoid model...
Autores principales: | , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8463074/ https://www.ncbi.nlm.nih.gov/pubmed/34463615 http://dx.doi.org/10.7554/eLife.66417 |
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author | Tindle, Courtney Fuller, MacKenzie Fonseca, Ayden Taheri, Sahar Ibeawuchi, Stella-Rita Beutler, Nathan Katkar, Gajanan Dattatray Claire, Amanraj Castillo, Vanessa Hernandez, Moises Russo, Hana Duran, Jason Crotty Alexander, Laura E Tipps, Ann Lin, Grace Thistlethwaite, Patricia A Chattopadhyay, Ranajoy Rogers, Thomas F Sahoo, Debashis Ghosh, Pradipta Das, Soumita |
author_facet | Tindle, Courtney Fuller, MacKenzie Fonseca, Ayden Taheri, Sahar Ibeawuchi, Stella-Rita Beutler, Nathan Katkar, Gajanan Dattatray Claire, Amanraj Castillo, Vanessa Hernandez, Moises Russo, Hana Duran, Jason Crotty Alexander, Laura E Tipps, Ann Lin, Grace Thistlethwaite, Patricia A Chattopadhyay, Ranajoy Rogers, Thomas F Sahoo, Debashis Ghosh, Pradipta Das, Soumita |
author_sort | Tindle, Courtney |
collection | PubMed |
description | BACKGROUND: SARS-CoV-2, the virus responsible for COVID-19, causes widespread damage in the lungs in the setting of an overzealous immune response whose origin remains unclear. METHODS: We present a scalable, propagable, personalized, cost-effective adult stem cell-derived human lung organoid model that is complete with both proximal and distal airway epithelia. Monolayers derived from adult lung organoids (ALOs), primary airway cells, or hiPSC-derived alveolar type II (AT2) pneumocytes were infected with SARS-CoV-2 to create in vitro lung models of COVID-19. RESULTS: Infected ALO monolayers best recapitulated the transcriptomic signatures in diverse cohorts of COVID-19 patient-derived respiratory samples. The airway (proximal) cells were critical for sustained viral infection, whereas distal alveolar differentiation (AT2→AT1) was critical for mounting the overzealous host immune response in fatal disease; ALO monolayers with well-mixed proximodistal airway components recapitulated both. CONCLUSIONS: Findings validate a human lung model of COVID-19, which can be immediately utilized to investigate COVID-19 pathogenesis and vet new therapies and vaccines. FUNDING: This work was supported by the National Institutes for Health (NIH) grants 1R01DK107585-01A1, 3R01DK107585-05S1 (to SD); R01-AI141630, CA100768 and CA160911 (to PG) and R01-AI 155696 (to PG, DS and SD); R00-CA151673 and R01-GM138385 (to DS), R01- HL32225 (to PT), UCOP-R00RG2642 (to SD and PG), UCOP-R01RG3780 (to P.G. and D.S) and a pilot award from the Sanford Stem Cell Clinical Center at UC San Diego Health (P.G, S.D, D.S). GDK was supported through The American Association of Immunologists Intersect Fellowship Program for Computational Scientists and Immunologists. L.C.A's salary was supported in part by the VA San Diego Healthcare System. This manuscript includes data generated at the UC San Diego Institute of Genomic Medicine (IGC) using an Illumina NovaSeq 6000 that was purchased with funding from a National Institutes of Health SIG grant (#S10 OD026929). |
format | Online Article Text |
id | pubmed-8463074 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-84630742021-09-27 Adult stem cell-derived complete lung organoid models emulate lung disease in COVID-19 Tindle, Courtney Fuller, MacKenzie Fonseca, Ayden Taheri, Sahar Ibeawuchi, Stella-Rita Beutler, Nathan Katkar, Gajanan Dattatray Claire, Amanraj Castillo, Vanessa Hernandez, Moises Russo, Hana Duran, Jason Crotty Alexander, Laura E Tipps, Ann Lin, Grace Thistlethwaite, Patricia A Chattopadhyay, Ranajoy Rogers, Thomas F Sahoo, Debashis Ghosh, Pradipta Das, Soumita eLife Medicine BACKGROUND: SARS-CoV-2, the virus responsible for COVID-19, causes widespread damage in the lungs in the setting of an overzealous immune response whose origin remains unclear. METHODS: We present a scalable, propagable, personalized, cost-effective adult stem cell-derived human lung organoid model that is complete with both proximal and distal airway epithelia. Monolayers derived from adult lung organoids (ALOs), primary airway cells, or hiPSC-derived alveolar type II (AT2) pneumocytes were infected with SARS-CoV-2 to create in vitro lung models of COVID-19. RESULTS: Infected ALO monolayers best recapitulated the transcriptomic signatures in diverse cohorts of COVID-19 patient-derived respiratory samples. The airway (proximal) cells were critical for sustained viral infection, whereas distal alveolar differentiation (AT2→AT1) was critical for mounting the overzealous host immune response in fatal disease; ALO monolayers with well-mixed proximodistal airway components recapitulated both. CONCLUSIONS: Findings validate a human lung model of COVID-19, which can be immediately utilized to investigate COVID-19 pathogenesis and vet new therapies and vaccines. FUNDING: This work was supported by the National Institutes for Health (NIH) grants 1R01DK107585-01A1, 3R01DK107585-05S1 (to SD); R01-AI141630, CA100768 and CA160911 (to PG) and R01-AI 155696 (to PG, DS and SD); R00-CA151673 and R01-GM138385 (to DS), R01- HL32225 (to PT), UCOP-R00RG2642 (to SD and PG), UCOP-R01RG3780 (to P.G. and D.S) and a pilot award from the Sanford Stem Cell Clinical Center at UC San Diego Health (P.G, S.D, D.S). GDK was supported through The American Association of Immunologists Intersect Fellowship Program for Computational Scientists and Immunologists. L.C.A's salary was supported in part by the VA San Diego Healthcare System. This manuscript includes data generated at the UC San Diego Institute of Genomic Medicine (IGC) using an Illumina NovaSeq 6000 that was purchased with funding from a National Institutes of Health SIG grant (#S10 OD026929). eLife Sciences Publications, Ltd 2021-08-13 /pmc/articles/PMC8463074/ /pubmed/34463615 http://dx.doi.org/10.7554/eLife.66417 Text en © 2021, Tindle et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Medicine Tindle, Courtney Fuller, MacKenzie Fonseca, Ayden Taheri, Sahar Ibeawuchi, Stella-Rita Beutler, Nathan Katkar, Gajanan Dattatray Claire, Amanraj Castillo, Vanessa Hernandez, Moises Russo, Hana Duran, Jason Crotty Alexander, Laura E Tipps, Ann Lin, Grace Thistlethwaite, Patricia A Chattopadhyay, Ranajoy Rogers, Thomas F Sahoo, Debashis Ghosh, Pradipta Das, Soumita Adult stem cell-derived complete lung organoid models emulate lung disease in COVID-19 |
title | Adult stem cell-derived complete lung organoid models emulate lung disease in COVID-19 |
title_full | Adult stem cell-derived complete lung organoid models emulate lung disease in COVID-19 |
title_fullStr | Adult stem cell-derived complete lung organoid models emulate lung disease in COVID-19 |
title_full_unstemmed | Adult stem cell-derived complete lung organoid models emulate lung disease in COVID-19 |
title_short | Adult stem cell-derived complete lung organoid models emulate lung disease in COVID-19 |
title_sort | adult stem cell-derived complete lung organoid models emulate lung disease in covid-19 |
topic | Medicine |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8463074/ https://www.ncbi.nlm.nih.gov/pubmed/34463615 http://dx.doi.org/10.7554/eLife.66417 |
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