Adult stem cell-derived complete lung organoid models emulate lung disease in COVID-19

Abstract

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.Method: 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).

When stem cells meet COVID-19: recent advances, challenges and future perspectives

“…Alveolar spheres infected with the virus can reflect the characteristics of the COVID-19 lungs, including interferon (IFN)-mediated inflammatory reactions, loss of surfactant proteins, and apoptosis. The results of the study by Tindle et al also validated a human lung model of COVID-19, which can be immediately used to study the pathogenesis of COVID-19 and to review new therapies and vaccines [ 100 ].…”

Organoids: An Emerging Tool to Study Aging Signature across Human Tissues. Modeling Aging with Patient-Derived Organoids

“…However, some biological aspects are unique to humans, and as a consequence, these models show limitations recapitulating human pathology. In that sense, PDOs emerged as a model to study cancer, infectious diseases, and inheritable genetic disorders [ 10 , 11 , 12 , 13 ]. The generation of organoids requires the use of stem cells, which can be either (a) pluripotent stem cells (PSCs)—embryonic stem cells (ESC) and induced pluripotent stem cells (iPSCs)—or (b) adult stem cells (ASCs) [ 7 , 8 , 9 , 13 ].…”

“…iPSCs have the potential to generate all three germ layers. Differentiation into distinct cell and tissue types can be controlled in vitro by the sequential use of different factors that mimic in vivo organ development [ 7 , 11 ]. In contrast, ASCs can be obtained from tissues with regenerative ability, and they have a limited differentiation potential.…”

The Potential Contribution of Biopolymeric Particles in Lung Tissue Regeneration of COVID-19 Patients

“…COVID-19 patient-derived respiratory samples from diverse cohorts were accurately recreated by infected ALO-monolayers. Both experiments were carried out in ALO monolayers with well-mixed proximodistal airway components [85]. Chronic viral infection requires the use of airway (proximal) cells, while terminal illness necessitated the use of distal alveolar differentiation (AT2AT1) cells to induce an unusually powerful host immune response.…”