MiR‐146a engineered extracellular vesicles derived from mesenchymal stromal cells more potently attenuate ischaemia–reperfusion injury in lung transplantation
Notice bibliographique
Résumé
BACKGROUND: The limited donor lung pool for lung transplantation (LTx) is largely due to concerns over ischaemia-reperfusion injury (IRI), a major cause of primary graft dysfunction (PGD). NLRP3 inflammasome activation is known to play a pivotal role in the onset of IRI. While human umbilical cord mesenchymal stromal cell-derived extracellular vesicles (hucMSC-EVs) have shown potential in reducing acute lung injury, their effects on NLRP3 activation in the context of LTx remain unclear. METHODS: In this study, engineered hucMSC-EVs were delivered via nebulisation to mitigate IRI in rat LTx models. We utilised both a rat orthotopic LTx model and a cell cold preservation reperfusion model to evaluate the therapeutic efficacy of hucMSC-EVs. Bulk-RNA sequencing, single-cell sequencing analysis, immunofluorescence and Western blot techniques were employed to assess NLRP3 inflammasome activation and inflammation. RESULTS: Nebulised hucMSC-EVs were efficiently internalised by alveolar macrophages (AMs), significantly reducing lung injury and improving oxygenation in the LTx models. Mechanistically, the engineered hucMSC-EVs, which enhance the expression of miR-146a, can more effectively suppress the activation of the NLRP3 inflammasome by targeting the IRAK1/TRAF6/NF-κB pathway, resulting in decreased levels of IL-1β, IL-18 and other inflammatory cytokines. These findings highlight the potential of miR-146a-modified EVs in modulating innate immune responses to alleviate IRI. CONCLUSION: Our results demonstrate that nebulised delivery of engineered hucMSC-EVs effectively mitigates IRI in LTx by inhibiting NLRP3 inflammasome activation. This innovative approach presents a promising strategy for enhancing donor lung preservation and improving post-transplant outcomes in LTx. HIGHLIGHTS: Nebulized Delivery of miR-146a Engineered hucMSC-EVs Mitigates Ischemia-Reperfusion Injury (IRI) in Lung Transplantation. This study demonstrates the therapeutic potential of nebulized, engineered human umbilical cord mesenchymal stromal cell-derived extracellular vesicles (hucMSC-EVs) modified with miR-146a to alleviate IRI in rat lung transplantation models. The treatment significantly improved lung oxygenation and reduced inflammation, highlighting the efficacy of this novel approach in enhancing donor lung preservation. Mechanistic Insights: Inhibition of NLRP3 Inflammasome Activation. Engineered hucMSC-EVs efficiently targeted alveolar macrophages and suppressed NLRP3 inflammasome activation through the IRAK1/TRAF6/NF-κB pathway. This modulation of innate immune responses played a crucial role in reducing IRI-induced lung injury and inflammation, offering a promising strategy to manage primary graft dysfunction in lung transplantation. Superior Efficacy of miR-146a-Modified EVs in Reducing Inflammatory Cytokines. The miR-146a modification enhanced the anti-inflammatory properties of hucMSC-EVs, leading to a more significant reduction in pro-inflammatory cytokines (IL-1β, IL-18, and TNF-α) compared to unmodified EVs. This targeted intervention presents a potential therapeutic avenue for improving lung transplant outcomes and mitigating IRI. Innovative Therapeutic Approach: Non-Invasive Nebulization for Direct Lung Delivery. The use of nebulized EVs for direct delivery to donor lungs represents a non-invasive and efficient method for lung-targeted therapy. This strategy could expand the applicability of MSC-EV-based treatments for improving lung transplantation outcomes, particularly in enhancing donor lung preservation during the procurement process.
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 distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,001 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 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 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 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 tête enseignante, 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 ».