Biology subjects

Foisset, F.

Publications and source records attributed to Foisset, F..

4 recordsLinked to original sources

bioRxiv2026

Influenza Virus Infection of an Immunocompetent Organotypic Model of the Human Respiratory Mucosa

Respiratory infectious diseases are among the leading causes of global morbidity and mortality and remain a major public health concern. Progress in understanding early host-pathogen interactions has been hampered by the limited physiological relevance of existing experimental systems. Different models mimicking the human respiratory epithelium have been developed to study viral infections in vitro, such as tridimensional (3D) tissue models and organoids. However, many lack key features of human tissue architecture, particularly the lamina propria or immune cells. To address these limitations, we established an immunocompetent 3D model of the human respiratory mucosa by combining nasal epithelial cells isolated from nasal brushings, fibroblasts from mid-turbinate nasal biopsies, and macrophages derived from blood monocytes. These cells were sequentially seeded into collagen-chitosan scaffolds, resulting in a reconstructed respiratory mucosa closely resembling the in vivo nasal tissues. To further confirm the physiological relevance of the model, we infected it with influenza A virus. The mucosa model supported viral replication in the epithelium and consequently showed increased secretion of inflammatory cytokines and upregulation of type I interferon related genes, enabling the monitoring of early antiviral innate immune responses in a physiologically relevant context.

bioengineering↗

bioRxiv2026

Ventral anterior foregut endoderm cells as progenitors for airway epithelial cell replacement in primary ciliary dyskinesia

BackgroundLung transplantation remains the ultimate treatment option for patients with end-stage lung disease, but has many limitations. This underlines the urgent need of developing alternative approaches to treat lung disorders. Among the emergent strategies, gene therapy holds great potential for the treatment of monogenic lung diseases. However, so far, aerosolized viral vector-based delivery for gene therapy has failed likely because of difficulties in accessing the target cells. Combined gene and cell therapy approaches could be a promising alternative. Trials using basal cell transplantation already showed encouraging results. Moreover, the induced pluripotent stem cell (iPSC) technology broadens the scope of personalized therapies by paving the way for autologous approaches. Our group previously derived iPSC lines from patients with Primary Ciliary Dyskinesia (PCD) and found that their correction by gene conversion allows functional recovery. This study aimed to identify the best progenitors and airway conditioning technique to develop an autologous cell replacement strategy for PCD. MethodsAirway epithelial cells were differentiated from induced pluripotent stem cell (iPSC) lines from a healthy donor (parental Hy03) and Hy03 in which MCIDAS was knocked out (PCD model) and maintained in air-liquid interface (iALI). The engraftment of GFP+ ventral Anterior Foregut Endoderm (vAFE) cells, differentiated from GFP-expressing Hy03 iPSCs, was assessed after conditioning of the recipient iALI. The efficacy (epithelial cell shedding) and toxicity (cell death) of different conditioning strategies were compared. Cilia functional repair was assessed using microbead motion tracking. ResultsGFP+ vAFE cells can successfully integrate and repair trypsin- or EDTA-conditioned airway epithelia derived from the parental and MCIDAS-/- Hy03 iPSC lines. EDTA showed optimal efficacy/safety balance. Progenitor integration and differentiation were confirmed by E-cadherin, tubulin-IV, KRT5 and MUC5AC co-expression in GFP+ engrafted cells at day 35 post-graft (immunofluorescence analysis). The engrafted GFP+ population reached 35-45% of the total epithelial population, as indicated by flow cytometry quantification of EpCAM+/GFP+ cells. Functional analysis demonstrated cilia motion restoration after GFP+ cell engraftment onto MCIDAS-/- iALI. ConclusionsOur study shows that vAFE cells can integrate and differentiate to repair epithelial models of PCD. EDTA conditioning is promising for the clinical application of this therapeutic strategy.

cell biology↗

bioRxiv2025

Human pluripotent stem cell-derived bronchial airway organoids provide insights into differential innate immune and long-term responses to SARS-CoV-2 infection in healthy and COPD.

Respiratory infections are a major global health concern, as underscored by the COVID-19 pandemic. To better understand bronchial tissue responses to viral infection, we have developed a preclinical in vitro model mimicking the multiciliated airway epithelium, from induced pluripotent stem cell (iPSC) and cultured in an air-liquid interface (iALI). By using iPSCs reprogrammed from patients with chronic obstructive pulmonary disease (COPD), we successfully generated a fully differentiated and functional bronchial epithelium exhibiting key COPD features with goblet and basal cell hyperplasia and tissue inflammation. SARS-CoV-2 could infected and replicated for several weeks in both healthy and COPD models, with a recurrent peak at 3 days after infection. Infected iALI exhibited cilia destruction and increased mucus secretion. Innate immune response of different infected iALI reveals a differential expression of interferon-stimulated genes (ISGs) and pro-inflammatory cytokine secretion. Notably, COPD iALI displayed an earlier innate immune response to SARS-CoV-2 infection as compared to healthy iALI, suggesting a genetic susceptibility of COPD iALI towards inflammation induced by SARS-CoV-2 infection, and a less efficient response to antivirals. In conclusion, our study demonstrates that the iALI bronchial organoid model is a powerful tool for investigating bronchial tissue responses to long term respiratory viral infections, antivirals, and patients with COPD or other airway pathology. Grapical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=151 SRC="FIGDIR/small/662440v1_ufig1.gif" ALT="Figure 1"> View larger version (53K): org.highwire.dtl.DTLVardef@9e5ef7org.highwire.dtl.DTLVardef@16ccf60org.highwire.dtl.DTLVardef@a2b29dorg.highwire.dtl.DTLVardef@17c6f14_HPS_FORMAT_FIGEXP M_FIG C_FIG HighLightsO_LIhiPSC-derived COPD airway organoids C_LIO_LISARS-CoV-2 productively infects induced pluripotent stem-cell derived bronchial organoids iALI and persisted over the long term C_LIO_LISARS-CoV-2 iALI infection results in cilia destruction, increased mucus secretion and a strong innate immune response C_LIO_LISARS-CoV-2 infection elicited a higher and earlier innate immune response in iCOPD C_LIO_LISARS-CoV-2 infection in iCOPD respond less to antivirals C_LI Short AbstractSARS-CoV-2 causes severe lower respiratory tract infection in COVID-19 patients, which can persist over time. Here, we used an in-house developed in vitro airway organoid derived from induced human pluripotent stem cells (iALI) to study SARS-CoV-2 infection over long term in healthy or COPD patients whom respiratory failure is at risk during infection. Our results show that SARS-CoV-2 infection results in high and lethal infection of bronchial epithelial cells, that persist over time, inducing mucus secretion, destruction of ciliated cells and specific cytokine release. A late innate immune response is observed in the healthy iALI, while in iCOPD, it appears earlier and stronger, suggesting a different sensing of SARS-CoV-2 in COPD patients, accompanied by a reduce sensitivity to antivirals. In conclusion, our study demonstrates that the iALI organoid model is a powerful tool for investigating bronchial tissue responses to long term respiratory viral infections, from healthy to pathologic patients.

cell biology↗

bioRxiv2023

Human airway ex vivo models: new tools to study the airway epithelial cell response to SARS-CoV-2 infection

Airway-liquid interface cultures of primary epithelial cells and of induced pluripotent stem cell-derived airway epithelial cells (ALI and iALI, respectively) are physiologically relevant models for respiratory virus infection studies because they can mimic the in vivo human bronchial epithelium. Here, we investigated gene expression profiles in human airway cultures (ALI and iALI models) infected or not with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) using publicly available and our own bulk and single-cell transcriptome datasets. SARS-CoV-2 infection significantly increased the expression of interferon-stimulated genes (IFI44, IFIT1, IFIT3, IFI35, IRF9, MX1, OAS1, OAS3 and ISG15) and inflammatory genes (NFKBIA, CSF1, FOSL1, IL32 and CXCL10) at day 4 post-infection, indicating activation of the interferon and immune responses to the virus. Extracellular matrix genes (ITGB6, ITGB1 and GJA1) also were altered in infected cells. Single-cell RNA sequencing data revealed that SARS-CoV-2 infection damaged the respiratory epithelium, particularly mature ciliated cells. The expression of genes encoding intercellular communication and adhesion proteins also was deregulated, suggesting a mechanism to promote shedding of infected epithelial cells. These data demonstrate that ALI/iALI models help to understand the airway epithelium response to SARS-CoV-2 infection and are a key tool for developing COVID-19 treatments.

cell biology↗