Adult Stem Cell-derived Complete Lung Organoid Models Emulate Lung Disease in COVID-19
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE165200 | GEO | 2021/01/20
REPOSITORIES: GEO
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Project description:The SARS-CoV-2 virus has already caused over a million COVID-19 cases and over fifty-thousand deaths globally. There is an urgent need to create novel models to study SARS-CoV-2 virus using human disease-relevant cells and tissues to understand key features of virus biology. We present a platform comprised of nine different cell and organoid derivatives from human pluripotent stem cells (hPSCs) representing all three primary germ layers, including lung progenitors and alveolar type II (AT2) cells, pancreatic endocrine cells, liver organoids, endothelial cells, cardiomyocytes, macrophages, microglia, and both cortical and dopaminergic neurons. We systematically probed which cell types are permissive to SARS-CoV-2 infection. Human pancreatic beta cells and hepatocytes were strikingly permissive to SARS-CoV-2 infection, further validated using adult primary human islets and liver organoids. Both in vitro and in a humanized mouse model, human lung progenitors and AT2 cells express the ACE2 viral receptor and were highly permissive to SARS-CoV-2 infection. Transcriptomic analysis following SARS-CoV-2 infection of hPSC-derived pancreatic and lung organoids revealed upregulation of chemokines but not type I/III interferon signaling, similar to what was seen in primary human COVID-19 pulmonary infection. Therefore, hPSC-derived cells phenocopy human COVID-19 disease and provide a valuable resource to understand SARS-CoV-2 biology and search for novel therapeutics.
2020-06-11 | GSE147903 | GEO
Project description:Human transmission of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), the causative pathogen of the coronavirus disease 2019 (COVID-19) pandemic, is exerting a massive health and socioeconomic burden. The virus infects pneumocytes, also known as alveolar epithelial type 2 (AT2) cells, leading to impaired gas exchange and acute lung injury, but the mechanisms driving infection and pathology are unclear. Here, we report a quantitative phosphoproteomic time-course survey of a validated human AT2 cell model, derived from induced pluripotent stem cells (iPSCs), that reveals rapid, profound and switch-like rewiring of lung cell functional modules upon SARS-CoV-2 infection. Maladaptive responses driven by viral propagation include altered host cell signaling pathways, remodeled host translational processes, impaired RNA processing, cytoskeletal-microtubule disruption coincident with interphase arrest, and a pronounced innate immune response. Our study provides a data-rich resource that defines the native host systems hijacked by SARS-CoV-2 and potential therapeutic avenues for COVID-19.
2020-11-20 | PXD020183 | Pride
Project description:Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, continues to spread around the world with serious cases and deaths. It has also been suggested that different genetic variants in the human genome affect both the susceptibility to infection and severity of disease in COVID-19 patients. Angiotensin-converting enzyme 2 (ACE2) has been identified as a cell surface receptor for SARS-CoV and SARS-CoV-2 entry into cells. The construction of an experimental model system using human iPS cells would enable further studies of the association between viral characteristics and genetic variants. Airway and alveolar epithelial cells are cell types of the lung that express high levels of ACE2 and are suitable for in vitro infection experiments. Here, we show that human iPS cell-derived airway and alveolar epithelial cells are highly susceptible to viral infection of SARS-CoV-2. Using gene knockout with CRISPR-Cas9 in human iPS cells we demonstrate that ACE2 plays an essential role in the airway and alveolar epithelial cell entry of SARS-CoV-2 in vitro. Replication of SARS-CoV-2 was strongly suppressed in ACE2 knockout (KO) lung cells. Our model system based on human iPS cell-derived lung cells may be applied to understand the molecular biology regulating viral respiratory infection leading to potential therapeutic developments for COVID-19 and the prevention of future pandemics.
2024-08-21 | GSE275240 | GEO
Project description:SARS-CoV-2 infects the respiratory tract, primarily causing pulmonary disease and cardiac complications described in many COVID-19 cases. To elucidate the molecular mechanisms of SARS-CoV-2 infection in the lung and heart, we conducted paired experiments in human stem cell-derived lung alveolar type II (AT2) epithelial cell and cardiac cultures, that were productively infected with SARS-CoV-2. SARS-CoV-2 variants of concern infected heart and lung cells with comparable efficiency. With CRISPR-Cas9 mediated knock-out of ACE2, we demonstrated that angiotensin converting enzyme 2 (ACE2) was essential for SARS-CoV-2 infection of both cell types. Further processing of the spike protein in lung cells required TMPRSS2 while infection of cardiac cells was achieved through the endosomal pathway and Cathepsin L. Host responses were significantly different, with a strong interferon response following infection in cardiac cells but not in lung AT2 cells. Transcriptome profiling and phosphoproteomics demonstrated that response to SARS-CoV-2 depended strongly on the cell type. We evaluated antiviral drugs that are approved for treatment of COVID-19, drugs that showed antiviral activity in vitro but were not found to be effective in clinical trials or are still under investigation and drugs targeting molecules identified in our molecular datasets in both cell types. We identified several antiviral compounds with distinct antiviral and toxicity profiles in lung AT2 and cardiac cells, highlighting the importance of using several relevant cell types for evaluation of antiviral drugs. Our data provide new insights into rational drug combinations for effective treatment of a virus that affects multiple organ systems.
2023-05-08 | PXD037615 | Pride
Project description:Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the global COVID-19 pandemic and the lack of therapeutics hinders pandemic control. Although lung disease is the primary clinical outcome in COVID-19 patients, how SARS-CoV-2 induces tissue pathology in the lung remains elusive. Here we describe a high-throughput-based platform to generate tens of thousands of self-organizing, nearly identical, and genetically matched human lung buds derived from human pluripotent stem cells (hPSCs) cultured on confined geometries on micropattern chips. Strikingly, in vitro-derived human lung buds resemble fetal human lung tissue and display in vivo-like proximo-distal coordination of alveolar and airway tissue differentiation whose 3D epithelial self-organization is directed by the levels of KGF. Single-cell transcriptomics unveiled the cell identities and ontogeny of airway and alveolar tissue and the specification of WNThi cycling alveolar stem cells from alveolar progenitors. These synthetic human lung buds are susceptible to SARS-CoV-2 infection and can be used to track cell type-dependent susceptibilities to infection, intercellular transmission and cytopathology in airway and alveolar tissue in individual synthetic lung buds. We detected an increased susceptibility to infection in alveolar cells and identified cycling alveolar stem cells as targets of SARS-CoV-2. We used this platform to test neutralizing antibodies isolated from convalescent plasma that efficiently blocked SARS-CoV-2 infection and intercellular transmission. Our platform offers unlimited, rapid and scalable access to disease-relevant lung tissue that recapitulate human lung development and can be used to track SARS-CoV-2 infection and identify pre-clinical candidate therapeutics for COVID-19.
2021-12-21 | GSE163698 | GEO
Project description:Viruses hijack host cell metabolism to acquire the building blocks required for viral replication. Understanding how SARS-CoV-2 alters host cell metabolism could lead to potential treatments for COVID-19, the disease caused by SARS-CoV-2 infection. Here we profile metabolic changes conferred by SARS-CoV-2 infection in kidney epithelial cells and lung air-liquid interface cultures and show that SARS-CoV-2 infection increases glucose carbon entry into the TCA cycle via increased pyruvate carboxylase expression. SARS-CoV-2 also reduces host cell oxidative glutamine metabolism while maintaining reductive carboxylation. Consistent with these changes in host cell metabolism, we show that SARS-CoV-2 increases activity of mTORC1, a master regulator of anabolic metabolism, in cell lines and patient lung stem cell-derived airway epithelial cells. We also show evidence of mTORC1 activation in COVID-19 patient lung tissue. Notably, mTORC1 inhibitors reduce viral replication in kidney epithelial cells and patient-derived lung stem cell cultures. This suggests that targeting mTORC1 could be a useful antiviral strategy for SARS-CoV-2 and treatment strategy for COVID-19 patients, although further studies are required to determine the mechanism of inhibition and potential efficacy in patients.
2021-02-19 | ST001709 | MetabolomicsWorkbench
Project description:Aging lungs are associated with several lung diseases, including chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis and pneumonia. This latter age-associated complication has been particularly prominent in the recent COVID-19 pandemic. We have analyzed carefully selected normal lung samples from human subjects at different ages simultaneously using hashtag-labeled samples and single cell RNA-sequencing technology. We identify prominent changes in macrophage populations in lungs from older individuals, including an emerging populations of macrophages expressing IFI27 and other interferon-regulated genes. We also see increased gene expression of CCL18 and other chemokines in FABP4+/alveolar and SPP1+/interstitial macrophages. All three macrophage populations highly express BSG/CD147a putative SARS-CoV-2 receptor and CSTL, a gene associated with SARS-CoV-2 activation. ACE2, the SARS-CoV-2 receptor, and TMPSS2, a SARS-CoV2 protease activator, are both expressed highly on AT2 cells with increased expression on AT2 cells from older lungs. AGTR2, a recently proposed alternative receptor for SARS-CoV-2 was highly selectively and markedly upregulated by AT2 cells from aging lungs. Thus, our data show increased lung expression of ACE2, AGTR2 and TMPRSS2 by AT2 cells with aging. In addition, our data indicate a distinct molecular pathway for lung SARS-CoV-2 infection of lung macrophages. Macrophages may contribute to increased COVID-19 severity in older patients by specific macrophage populations poised to contribute to the cytokine storm, in particular through enhanced interferon responses and interleukin-6 production.
2024-05-06 | GSE150148 | GEO
Project description:The airways and the alveoli of the human respiratory tract are lined by two distinct types of epithelium. We previously established long-term expanding human lung epithelial organoids from lung tissues and developed a ‘proximal’ differentiation protocol to generate mucociliary airway organoids, yet the derivation of alveolar organoids from adult lung has remained a challenge. Here we defined a ‘distal’ differentiation approach to generate alveolar organoids from the same source that allows the establishment of airway organoids. Alveolar organoids are enriched for AT1 and AT2 cells and functionally simulate the alveolar epithelium. AT2 cells in lung organoids act as the progenitor cells from which alveolar organoids emerge. Moreover, we demonstrate productive SARS-CoV-2 infection of alveolar organoids. We further optimize 2-dimensional (2D) airway organoids. When differentiated under a slightly acidic pH, these 2D airway organoids sustain enhanced viral replication and better recapitulate the high infectivity of SARS-CoV-2. Moreover, the optimized 2D airway organoids can model IgG transcytosis across the airway epithelium. Collectively, we establish a bipotential organoid culture system that can reproducibly expand the entire human respiratory epithelium in vitro for modeling respiratory diseases, including COVID-19.
2022-06-22 | GSE189514 | GEO
Project description:Male sex belongs to one of the risk factors for severe COVID-19 outcome. However, underlying mechanisms that could affect sex dependent disease outcome are yet unknown. Here, we identified the CYP19A1 gene encoding for the testosterone-to-estradiol metabolizing enzyme CYP19A1 (alias aromatase) as a host factor that contributes to worsened disease outcome in male hamsters. SARS-CoV-2 infection increases CYP19A1 transcription most prominently in the lungs of male animals, which correlates with reduced circulating testosterone and increased circulating estradiol levels. Dysregulated sex hormone levels in male golden hamsters are associated with reduced lung function compared to females. Treatment of SARS-CoV-2 infected hamsters with letrozole, a clinically approved CYP19A1 inhibitor, supported recovery of dysregulated sex hormone levels and was associated with improved lung function in male but not female animals compared to placebo controls. Whole-lung transcriptome analysis in letrozole treated versus placebo treated control groups revealed key pathways associated with improved lung health in males. To seek translation of these findings into humans, we analyzed autopsy-derived lung samples of COVID-19 cases from three independent study sites. We found that CYP19A1 transcription and protein expression is strongly elevated in the lungs of men who died with COVID-19 as compared to females or non-COVID-19 controls. Our findings highlight the role of the lung as a yet unrecognized but critical organ involved in metabolic responses against respiratory virus infections. Furthermore, inhibition of CYP19A1 by the clinically approved drug letrozole may pose a new therapeutic strategy to reduce poor long-term COVID-19 outcome.
2022-01-21 | E-MTAB-11162 | biostudies-arrayexpress
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2020-11-06 | GSE160435 | GEO