Mechanodynamic Alveolar Epithelial-fibroblast Models Via the Flexcell to Study Mechanical-induced Inflammatory and Fibrotic Mechanisms in Lung Disease
Notice bibliographique
Résumé
Abstract Rationale Mechanical strain plays a significant role in lung physiology and pathophysiology, influencing cellular behavior, tissue homeostasis, and mechanisms of disease such as inflammation and fibrosis Current in-vitro models, particularly 2D monolayers and animal models, fail to capture the complexity of the lung's mechanodynamic environment. This study addressed this gap by developing advanced mechanodynamic 2D and 3D alveolar epithelial-fibroblast co-cultures and organoids to mimic the lung, using the unique Flexcell bioreactor that enables the application of strain to mimic the mechanical lung environment. Methods Human alveolar epithelial cells (A549) and lung fibroblasts (MRC-5) were used to establish 2D co-cultures in BioFlex plates as well as 3D alveolar co-cultures and organoids embedded in collagen-I-gels in Tissue Train plates. The models were then subjected to equibiaxial strain of 18% amplitude at 0.4Hz using the Flexcell tension system to mimic a pathological strain environment. The impact of mechanical strain on cell proliferation, morphology, cytoskeletal & tight junctional protein expression, IL-6 & IL-8 inflammatory cytokine release, and cell-viability were assessed via immunocytochemistry & confocal imaging, cell counts & identification, ELISAs, and lactate dehydrogenase (LDH) assays. Results Mechanical strain of 18%, 0.4Hz, significantly caused predominantly increased cell proliferation rates in 3D co-culture models but not in 2D epithelial cell and fibroblast monolayers and co-cultures. Morphological analysis revealed a marked transition of fibroblasts into the broadened-shaped cells under strain, indicating myofibroblast differentiation in the 3D co-cultures. This was in line with increased F-actin in 3D co-cultures compared to decreased F-actin expression in epithelial cells and fibroblasts in 2D models after pathological strain. The expression of the tight junctional protein ZO-1 was decreased after strain in all 2D and 3D models. Further, there was increased release of pro-inflammatory cytokines, IL-6 and IL-8, in response to strain, and increased strain-induced cell death in all models, which was further heightened in 3D cultures. Conclusion This study demonstrated that in vitro mechanical multicellular alveolar models mimic the mechanodynamic lung environment. Specifically, 3D alveolar models in the Flexcell bioareactor provide a 3D configuration and multicellular environment necessary to replicate the in vivo mechanodynamic lung tissue, highlighting their importance for studying strain-induced cellular responses in line with inflammatory and fibrotic mechanisms in lung diseases. The developed models provide a valuable platform for exploring the mechanisms underlying lung disease progression and for testing therapeutic interventions aimed at restoring normal cellular responses to fatal injury from aberrant mechanical forces.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,001 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,001 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».