Mesenchymal Stromal Cell Microparticles Enhance Lung Endothelial Barrier Through CD44 and the S1P/ceramide Rheostat
Bibliographic record
Abstract
Introduction Acute respiratory distress syndrome (ARDS) is a fatal condition characterized by hyperinflammation and pulmonary microvascular leak. Treatment is only supportive with no pharmacological cure. Recently, mesenchymal stromal/stem cells (MSCs) have emerged as potential therapy, but greater knowledge on their mechanism(s) of action could yield development of cell‐free therapeutics. Objective To determine if MSC‐produced microparticles (MPs) ameliorate endothelial barrier disruption and identify their biomolecular contents responsible for such therapeutic effect. Methods To re‐capitulate lung capillary leak in ARDS, primary human pulmonary microvascular endothelial cell (HPMEC) monolayers grown on Transwell inserts were injured with thrombin to induce barrier disruption as measured by transendothelial electrical resistance (TEER). MPs were purified out of conditioned medium produced by MSCs either stimulated with Ca 2+ ionophore or unstimulated. MPs were administered to treat thrombin‐injured HPMEC monolayers; surface markers were compared by flow cytometry and lipid content analyzed by HPLC‐MS. Results MPs from unstimulated MSCs enhanced HPMEC barrier function and TEER recovery after thrombin injury, while MPs from stimulated MSCs were injurious. Stimulated MSCs produced MPs with significantly less surface CD44. Antibody blockade of CD44 on unstimulated MPs eliminated their therapeutic effect on HPMEC monolayers. Moreover, stimulated MPs had significantly more total ceramides and less sphingosine‐1‐phosphate (S1P) than unstimulated MPs. Ceramide degradation by neutral ceramidase blunted the injurious effect of stimulated MPs. The therapeutic function of unstimulated MPs was eliminated with ceramide over‐production by acid sphingomyelinase or S1P degradation by S1P lyase. Conclusion These results show MSC‐produced MPs were therapeutic after lung capillary endothelial barrier disruption. Beneficial effects were associated with surface CD44 and greater ratio of S1P:ceramide content. This knowledge provides a mechanistic basis for development of MSC‐based cell‐free therapeutics. Support or Funding Information This work was supported by Ontario Research Fund and Canadian Institutes of Health Research. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".