Human disease models in drug development

Nature Reviews Bioengineering, Journal Year: 2023, Volume and Issue: 1(8), P. 545 - 559

Published: May 11, 2023

Language: Английский

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Respiratory epithelial cell responses to SARS-CoV-2 in COVID-19

Thorax, Journal Year: 2021, Volume and Issue: 77(2), P. 203 - 209

Published: Aug. 17, 2021

COVID-19 has different clinical stages, and effective therapy depends on the location extent of infection. The purpose this review is to provide a background for understanding progression disease throughout pulmonary epithelium discuss therapeutic options. prime sites infection that will be contrasted in are conducting airways gas exchange portions lung. These two characterised by distinct cellular composition innate immune responses, which suggests use agents. In nose, ciliated cells primary target SARS-CoV-2 viral infection, replication release. Infected shed their cilia, disables mucociliary clearance. Evidence further points suppressed or incompletely activated response upper airways. Asymptomatic individuals can still have productive infect others. portion lung, alveolar type II epithelial cell main type. Cell death marked during likely contribute damage resultant acute respiratory distress syndrome. Alveolar precipitate hyperinflammatory state, many therapies severe COVID-19. Disease resolution lung variable may include scaring long-term sequalae because also progenitor epithelium.

Language: Английский

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Revealing Tissue-Specific SARS-CoV-2 Infection and Host Responses using Human Stem Cell-Derived Lung and Cerebral Organoids

Stem Cell Reports, Journal Year: 2021, Volume and Issue: 16(3), P. 437 - 445

Published: Feb. 15, 2021

COVID-19 is a transmissible respiratory disease caused by novel coronavirus, SARS-CoV-2, and has become global health emergency. There an urgent need for robust practical in vitro model systems to investigate viral pathogenesis. Here, we generated human induced pluripotent stem cell (iPSC)-derived lung organoids (LORGs), cerebral (CORGs), neural progenitor cells (NPCs), neurons, astrocytes. LORGs containing epithelial cells, alveolar types 1 2, highly express ACE2 TMPRSS2 are permissive SARS-CoV-2 infection. infection induces interferons, cytokines, chemokines activates critical inflammasome pathway genes. Spike protein inhibitor, EK1 peptide, inhibitors (camostat/nafamostat) block entry LORGs. Conversely, CORGs, NPCs, astrocytes, neurons low levels of correspondingly not Infection neuronal TLR3/7, OAS2, complement system, apoptotic These findings will aid understanding pathogenesis facilitate drug discovery.

Language: Английский

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Lessons in self-defence: inhibition of virus entry by intrinsic immunity

Nature reviews. Immunology, Journal Year: 2021, Volume and Issue: 22(6), P. 339 - 352

Published: Oct. 13, 2021

Language: Английский

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Disparate temperature-dependent virus–host dynamics for SARS-CoV-2 and SARS-CoV in the human respiratory epithelium

PLoS Biology, Journal Year: 2021, Volume and Issue: 19(3), P. e3001158 - e3001158

Published: March 29, 2021

Since its emergence in December 2019, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has spread globally and become a major public health burden. Despite close phylogenetic relationship to SARS-CoV, SARS-CoV-2 exhibits increased human-to-human transmission dynamics, likely due efficient early replication the upper respiratory epithelium of infected individuals. different temperatures encountered human lower tract (33°C 37°C, respectively) have been shown affect kinetics several viruses, as well host innate immune response we investigated impact temperature on SARS-CoV infection using primary airway epithelial cell culture model. SARS-CoV-2, contrast replicated higher titers when infections were performed at 33°C rather than 37°C. Although both viruses highly sensitive type I III interferon pretreatment, detailed time-resolved transcriptome analysis revealed temperature-dependent pro-inflammatory responses induced by that inversely proportional efficiency or These data provide crucial insight pivotal virus-host interaction dynamics are line with characteristic clinical features their respective efficiencies.

Language: Английский

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Induced Pluripotent Stem Cells (iPSCs)—Roles in Regenerative Therapies, Disease Modelling and Drug Screening

Cells, Journal Year: 2021, Volume and Issue: 10(9), P. 2319 - 2319

Published: Sept. 5, 2021

The discovery of induced pluripotent stem cells (iPSCs) has made an invaluable contribution to the field regenerative medicine, paving way for identifying true potential human embryonic (ESCs). Since controversy around ethicality ESCs continue be debated, iPSCs have been used circumvent process destruction embryo. use transformed biological research, wherein increasing number studies are documenting nuclear reprogramming strategies make them beneficial models drug screening as well disease modelling. flexibility include compatibility non-invasive harvesting, and ability source from patients with rare diseases. widely in cardiac modelling, studying inherited arrhythmias, neural disorders including Alzheimer's disease, liver spinal cord injury. Extensive research factors that involved maintaining identity during induction pluripotency somatic is undertaken. focus current review detail all clinical translation strength its ever-growing space.

Language: Английский

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Genome-wide bidirectional CRISPR screens identify mucins as host factors modulating SARS-CoV-2 infection

Nature Genetics, Journal Year: 2022, Volume and Issue: 54(8), P. 1078 - 1089

Published: July 25, 2022

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes a range of symptoms in infected individuals, from mild illness to distress syndrome. A systematic understanding host factors influencing viral infection is critical elucidate SARS-CoV-2-host interactions and the progression Coronavirus disease 2019 (COVID-19). Here, we conducted genome-wide CRISPR knockout activation screens human lung epithelial cells with endogenous expression SARS-CoV-2 entry ACE2 TMPRSS2. We uncovered proviral antiviral across highly interconnected pathways, including clathrin transport, inflammatory signaling, cell-cycle regulation, transcriptional epigenetic regulation. further identified mucins, family high molecular weight glycoproteins, as prominent restriction network that inhibits vitro murine models. These mucins also inhibit diverse viruses. This functional landscape provides physiologically relevant starting point for new host-directed therapeutics highlights airway defense mechanism.

Language: Английский

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Human organoid models to study SARS-CoV-2 infection

Nature Methods, Journal Year: 2022, Volume and Issue: 19(4), P. 418 - 428

Published: April 1, 2022

Language: Английский

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Generation of human alveolar epithelial type I cells from pluripotent stem cells

Cell stem cell, Journal Year: 2024, Volume and Issue: 31(5), P. 657 - 675.e8

Published: April 19, 2024

Alveolar epithelial type I cells (AT1s) line the gas exchange barrier of distal lung and have been historically challenging to isolate or maintain in cell culture. Here, we engineer a human vitro AT1 model system via directed differentiation induced pluripotent stem (iPSCs). We use primary adult global transcriptomes suggest benchmarks pathways, such as Hippo-LATS-YAP/TAZ signaling, enriched these cells. Next, generate iPSC-derived alveolar II (AT2s) find that nuclear YAP signaling is sufficient promote broad transcriptomic shift from AT2 gene programs. The resulting express molecular, morphologic, functional phenotype reminiscent cells, including capacity form flat producing characteristic extracellular matrix molecules secreted ligands. Our results provide an potential source AT1s.

Language: Английский

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Human airway cells prevent SARS-CoV-2 multibasic cleavage site cell culture adaptation

eLife, Journal Year: 2021, Volume and Issue: 10

Published: April 9, 2021

Virus propagation methods generally use transformed cell lines to grow viruses from clinical specimens, which may force rapidly adapt culture conditions, a process facilitated by high viral mutation rates. Upon in VeroE6 cells, SARS-CoV-2 mutate or delete the multibasic cleavage site (MBCS) spike protein. Previously, we showed that MBCS facilitates serine protease-mediated entry into human airway cells (Mykytyn et al., 2021). Here, report propagating on line Calu-3 – expresses proteases prevents adaptations and directly adjacent (S686G). Similar results were obtained using organoid-based system for propagation. Thus, in-depth knowledge biology of virus can be used establish prevent adaptation.

Language: Английский

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