Ca <sup>2+</sup> Signaling and Barrier Function of Lung Microvascular Endothelial Cells are Modulated by Mesenchymal Stromal Cell Microparticles
Notice bibliographique
Résumé
Introduction Acute respiratory distress syndrome (ARDS) is a fatal condition characterized by hyperinflammation and pulmonary microvascular leak. With no pharmacological cure, treatment remains only supportive. Mesenchymal stromal cells (MSCs) have recently generated excitement as a potential therapy, presumably functioning through paracrine mechanisms which may rely on the release of extracellular vesicles like microparticles (MPs). However, the mechanism by which MPs modulate the pathology of ARDS is poorly understood yet may pave the way to develop cell‐free cell therapeutics. Objective To identify the mechanism(s) by which MSC derived MPs enhance pulmonary microvascular barrier function. Methods MPs were purified from conditioned medium produced by MSCs either stimulated with Ca 2+ ionophore or unstimulated. Monolayers of primary human pulmonary microvascular endothelial cells (HPMECs) were injured with thrombin to induce barrier disruption, measured by transendothelial electrical resistance (TEER), mimicking lung microvascular leak as observed in ARDS. MPs were administered to treat thrombin‐injured HPMECs and changes in intracellular Ca 2+ concentration ([Ca 2+ ] i ) were determined by ratiometric imaging of Fura‐2. Results Thrombin administered to HPMECs caused an initial, brief spike in [Ca 2+ ] i followed by a second phase characterized as a prolonged, gradual increase in [Ca 2+ ] i . Following the thrombin‐induced [Ca 2+ ] i spike, treatment with MPs from unstimulated MSCs eliminated the second phase and caused a sustained, decrease in [Ca 2+ ] i below baseline. In parallel, MPs from unstimulated MSCs enhanced TEER recovery and VE‐cadherin integrity in intercellular junctions of HPMECs following thrombin‐induced permeability. Conversely, treatment with MPs from Ca 2+ ionophore stimulated MSCs amplified the second phase of the [Ca 2+ ] i response to thrombin and prevented recovery of HPMEC barrier function. HPLC‐MS revealed MPs from unstimulated MSCs had lower ceramide and higher sphingosine‐1‐phosphate (S1P) content than MPs from Ca 2+ ionophore stimulated MSCs. S1P degradation by S1P lyase or blockade of the S1P receptor 1 attenuated the barrier‐protective effect of MPs from unstimulated MSCs, while ceramide degradation by neutral ceramidase improved barrier recovery following treatment with MPs from Ca 2+ ionophore stimulated MSCs. Conclusion MPs from unstimulated MSCs therapeutically enhance lung capillary barrier function, presumably by attenuating endothelial [Ca 2+ ] i responses by resetting the ceramide/S1P rheostat. These findings provide a mechanistic basis for development and optimization/enrichment of MSC derived MPs as a promising cell‐free cell therapy for ARDS. Support or Funding Information This work was supported by the Ontario Research Fund and Canadian Institutes of Health Research. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .
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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 | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 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 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,001 | 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 ».