Organoids as a Powerful Model for Respiratory Diseases

Liu, Yu; Wu, Qi; Sun, Xin; Shen, Jun; Chen, Huaiyong

doi:10.1155/2020/5847876

Cited by 52 publications

(42 citation statements)

References 75 publications

(95 reference statements)

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“…SARS-CoV-2 is primarily a respiratory infection which can lead to multi-organ failure and organoids can be used to investigate the causes and rapid testing of potential therapies. Importantly, human lung organoids have been developed 211,212 and used to study respiratory infections including IAV and tuberculosis, 213 and will be important for investigating COVID-19 pathogenesis. One study used pluripotent stem cell-derived lung organoids and identified drug candidates including imatinib and mycophenolic acid, that inhibited SARS-CoV-2 entry.…”

Section: Organoidsmentioning

confidence: 99%

Animal and translational models of SARS-CoV-2 infection and COVID-19

et al. 2020

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COVID-19 is causing a major once-in-a-century global pandemic. The scientific and clinical community is in a race to define and develop effective preventions and treatments. The major features of disease are described but clinical trials have been hampered by competing interests, small scale, lack of defined patient cohorts and defined readouts. What is needed now is head-to-head comparison of existing drugs, testing of safety including in the background of predisposing chronic diseases, and the development of new and targeted preventions and treatments. This is most efficiently achieved using representative animal models of primary infection including in the background of chronic disease with validation of findings in primary human cells and tissues. We explore and discuss the diverse animal, cell and tissue models that are being used and developed and collectively recapitulate many critical aspects of disease manifestation in humans to develop and test new preventions and treatments.

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Section: Organoidsmentioning

confidence: 99%

Animal and translational models of SARS-CoV-2 infection and COVID-19

et al. 2020

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“…Previously reported hAEC2 organoids have utilized MRC5, a fetal human lung fibroblasts cell line, as feeders to maintain hAEC2s in vitro (Barkauskas et al, 2013;Li et al, 2020;Zacharias et al, 2018). We initially hypothesized that co-culture with primary adult human lung mesenchyme (AHLM) would improve the growth of hAEC2 organoids compared to MRC5.…”

Section: Primary Adult Human Lung Mesenchyme Drives Human Aec2 Transdmentioning

confidence: 99%

Human alveolar Type 2 epithelium transdifferentiates into metaplastic KRT5+ basal cells during alveolar repair

Kathiriya

Wang

Brumwell

et al. 2020

Preprint

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Understanding differential lineage potential of orthologous stem cells across species can shed light on human disease. Here, utilizing 3D organoids, single cell RNAseq, and xenotransplants, we demonstrate that human alveolar type 2 cells (hAEC2s), unlike murine AEC2s, are multipotent and able to transdifferentiate into KRT5+ basal cells when co-cultured with primary fibroblasts in 3D organoids. Trajectory analyses and immunophenotyping of epithelial progenitors in idiopathic pulmonary fibrosis (IPF) indicate that hAEC2s transdifferentiate into metaplastic basal cells through alveolarbasal intermediate (ABI) cells that we also identify in hAEC2-derived organoids.Modulating hAEC2-intrinsic and niche factors dysregulated in IPF can attenuate metaplastic basal cell transdifferentiation and preserve hAEC2 identity. Finally, hAEC2stransplanted into fibrotic immune-deficient murine lungs engraft as either hAEC2s or differentiated KRT5+ basal cells. Our study indicates that hAEC2s-loss and expansion of alveolar metaplastic basal cells in IPF are causally connected, which would not have been revealed utilizing murine AEC2s as a model. Key wordsHuman stem cells; alveolar type 2 cells (AEC2s); metaplasia; idiopathic pulmonary fibrosis (IPF); KRT5+ basal cells; alveolar-basal intermediate cell (ABI) Highlights •Human AEC2s transdifferentiate into KRT5+ basal cells when accompanied by primary adult human lung mesenchyme in 3D organoid culture.• Alterations of hAEC2-intrinsic and niche factors dysregulated in IPF can modify metaplastic hAEC2 transdifferentiation.• hAEC2s engraft into fibrotic lungs of immune-deficient mice and transdifferentiate into metaplastic basal cells.• Transcriptional trajectory analysis suggests that hAEC2s in IPF gives rise to metaplastic basal cells via alveolar-basal intermediate cells.

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“…Thus, the lung AT2 cells which are likely the SARS-CoV-2's target are also the producers of the surfactant proteins. Depletion of AT2 cells due to SARS-CoV-2 infection, or other pathogens that targeting the AT2 CELLS, is therefore expected to cause surfactant deficit, which has previously been shown to be associated with incomplete repair of injured alveolar epithelium and fibrotic elimination [20]. Similar to surfactant deficit, the main histological finding from autopsies taken from lungs of COVID-19 patients includes injury to the alveolar epithelial cells and fibrosis [48].…”

Section: Discussionmentioning

confidence: 99%

“…The surfactant proteins, encoded by the SFTPs genes, are expressed and produced by the AT2 cells and are essential to maintaining lung homeostasis. Deficiency in these genes has been found to cause idiopathic pulmonary fibrosis and incomplete repair of injured alveolar epithelium, mainly in older adults [20,21]. Interestingly, SARS-CoV-2 host receptor, ACE2, was also found to be expressed by AT2 cells [46].…”

Section: Discussionmentioning

confidence: 99%

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Age- and sex-transcriptome analysis provide evidences for the sex biases in the pathogenesis of COVID-19 and other respiratory infectious diseases

Gershoni¹

2020

Preprint

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Age and sex were shown to affect the prevalence and the manifestation of many respiratory infectious diseases. These can be attributed to age and sex related alterations in the immune system and in the lung functions. Since the outbreak of COVID-19, epidemiological studies consistently report that age and sex are major risk factors in both morbidity and mortality due to COVID-19. Thus, understanding age and sex dependent gene expression in the lung and in the immune system can provide mechanical evidences with respects to sex related higher risk of elderly to develop severe complications in respiratory infectious diseases. In this context, sex- and age- transcriptome analysis from hundreds of lung and blood samples, revealed significant downregulation of the lung surfactant and blood innate immune genes, that occur predominantly in elderly men. Depletion in lung surfactant leads to enhanced injury of alveolar epithelium and fibrotic destruction, and recruitment of the innate immune system is essential to control infection of new pathogens like SARS-CoV-2. Interestingly, surfactant proteins, which protect the lung from infection, are co-produced with the SARS-CoV-2 host receptor- ACE2, by the AT2 cells. Thus, infection by SARS-CoV-2 is expected to lead to decline in AT2 cells and a loss of surfactant proteins, especially in elderly men.

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Organoids as a Powerful Model for Respiratory Diseases

Cited by 52 publications

References 75 publications

Animal and translational models of SARS-CoV-2 infection and COVID-19

Animal and translational models of SARS-CoV-2 infection and COVID-19

Human alveolar Type 2 epithelium transdifferentiates into metaplastic KRT5+ basal cells during alveolar repair

Age- and sex-transcriptome analysis provide evidences for the sex biases in the pathogenesis of COVID-19 and other respiratory infectious diseases

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