Human mesenchymal stromal cell-secreted lactate induces M2-macrophage differentiation by metabolic reprogramming
Bibliographic record
Abstract
// Silvia Selleri 1,2,* , Panojot Bifsha 1,2,* , Sara Civini 3 , Consiglia Pacelli 4 , Mame Massar Dieng 1,5 , William Lemieux 1,2 , Ping Jin 3 , Renée Bazin 6 , Natacha Patey 7 , Francesco M. Marincola 3,8 , Florina Moldovan 1,9 , Charlotte Zaouter 1 , Louis-Eric Trudeau 4 , Basma Benabdhalla 1 , Isabelle Louis 1,10 , Christian Beauséjour 1,4 , David Stroncek 3 , Françoise Le Deist 1,2,10 and Elie Haddad 1,2,10 1 CHU Sainte-Justine Research Center, Montreal, QC, Canada 2 Department of Microbiology, Infectiology and Immunology, University of Montreal, Montreal, QC, Canada 3 Department of Transfusion Medicine, Clinical Center, NIH, Bethesda, MD, USA 4 Department of Pharmacology, University of Montreal, Montreal, QC, Canada 5 Department of Biology, New York University, Abu Dhabi, United Arab Emirates 6 Department of Research and Development, Héma-Québec, Québec, QC, Canada 7 Department of Pathology, University of Montreal, Montreal, QC, Canada 8 Sidra Medical and Research Center, Doha, Qatar 9 Faculty of Dentistry, University of Montreal, Montreal, QC, Canada 10 Department of Pediatrics, University of Montreal, Montreal, QC, Canada * These authors have contributed equally to this work Correspondence to: Elie Haddad, email: // Keywords : mesenchymal stromal cells, dendritic cell differentiation, M2-macrophages, lactate, metabolism, Immunology and Microbiology Section, Immune response, Immunity Received : August 10, 2015 Accepted : March 26, 2016 Published : April 06, 2016 Abstract Human mesenchymal stromal cells (MSC) have been shown to dampen immune response and promote tissue repair, but the underlying mechanisms are still under investigation. Herein, we demonstrate that umbilical cord-derived MSC (UC-MSC) alter the phenotype and function of monocyte-derived dendritic cells (DC) through lactate-mediated metabolic reprogramming. UC-MSC can secrete large quantities of lactate and, when present during monocyte-to-DC differentiation, induce instead the acquisition of M2-macrophage features in terms of morphology, surface markers, migratory properties and antigen presentation capacity. Microarray expression profiling indicates that UC-MSC modify the expression of metabolic-related genes and induce a M2-macrophage expression signature. Importantly, monocyte-derived DC obtained in presence of UC-MSC, polarize naïve allogeneic CD4 + T-cells into Th2 cells. Treatment of UC-MSC with an inhibitor of lactate dehydrogenase strongly decreases lactate concentration in culture supernatant and abrogates the effect on monocyte-to-DC differentiation. Metabolic analysis further revealed that UC-MSC decrease oxidative phosphorylation in differentiating monocytes while strongly increasing the spare respiratory capacity proportional to the amount of secreted lactate. Because both MSC and monocytes are recruited in vivo at the site of tissue damage and inflammation, we propose the local increase of lactate concentration induced by UC-MSC and the consequent enrichment in M2-macrophage generation as a mechanism to achieve immunomodulation.
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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 | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
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".