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...
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eLife Sciences Publications Ltd
2021
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oai:doaj.org-article:a2f6ea2e6df643eab8feb143e88606342021-11-16T14:07:11ZAdult stem cell-derived complete lung organoid models emulate lung disease in COVID-1910.7554/eLife.664172050-084Xe66417https://doaj.org/article/a2f6ea2e6df643eab8feb143e88606342021-08-01T00:00:00Zhttps://elifesciences.org/articles/66417https://doaj.org/toc/2050-084XBackground: 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).Courtney TindleMacKenzie FullerAyden FonsecaSahar TaheriStella-Rita IbeawuchiNathan BeutlerGajanan Dattatray KatkarAmanraj ClaireVanessa CastilloMoises HernandezHana RussoJason DuranLaura E Crotty AlexanderAnn TippsGrace LinPatricia A ThistlethwaiteRanajoy ChattopadhyayThomas F RogersDebashis SahooPradipta GhoshSoumita DaseLife Sciences Publications Ltdarticlelung organoidSARS-CoV2disease modelingcomputationalimmune responseAT2 differentiationMedicineRScienceQBiology (General)QH301-705.5ENeLife, Vol 10 (2021) |
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DOAJ |
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DOAJ |
| language |
EN |
| topic |
lung organoid SARS-CoV2 disease modeling computational immune response AT2 differentiation Medicine R Science Q Biology (General) QH301-705.5 |
| spellingShingle |
lung organoid SARS-CoV2 disease modeling computational immune response AT2 differentiation Medicine R Science Q Biology (General) QH301-705.5 Courtney Tindle MacKenzie Fuller Ayden Fonseca Sahar Taheri Stella-Rita Ibeawuchi Nathan Beutler Gajanan Dattatray Katkar Amanraj Claire Vanessa Castillo Moises Hernandez Hana Russo Jason Duran Laura E Crotty Alexander Ann Tipps Grace Lin Patricia A Thistlethwaite Ranajoy Chattopadhyay Thomas F Rogers Debashis Sahoo Pradipta Ghosh Soumita Das Adult stem cell-derived complete lung organoid models emulate lung disease in COVID-19 |
| 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 |
article |
| author |
Courtney Tindle MacKenzie Fuller Ayden Fonseca Sahar Taheri Stella-Rita Ibeawuchi Nathan Beutler Gajanan Dattatray Katkar Amanraj Claire Vanessa Castillo Moises Hernandez Hana Russo Jason Duran Laura E Crotty Alexander Ann Tipps Grace Lin Patricia A Thistlethwaite Ranajoy Chattopadhyay Thomas F Rogers Debashis Sahoo Pradipta Ghosh Soumita Das |
| author_facet |
Courtney Tindle MacKenzie Fuller Ayden Fonseca Sahar Taheri Stella-Rita Ibeawuchi Nathan Beutler Gajanan Dattatray Katkar Amanraj Claire Vanessa Castillo Moises Hernandez Hana Russo Jason Duran Laura E Crotty Alexander Ann Tipps Grace Lin Patricia A Thistlethwaite Ranajoy Chattopadhyay Thomas F Rogers Debashis Sahoo Pradipta Ghosh Soumita Das |
| author_sort |
Courtney Tindle |
| title |
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_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_sort |
adult stem cell-derived complete lung organoid models emulate lung disease in covid-19 |
| publisher |
eLife Sciences Publications Ltd |
| publishDate |
2021 |
| url |
https://doaj.org/article/a2f6ea2e6df643eab8feb143e8860634 |
| work_keys_str_mv |
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