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Human mesenchymal stromal cell-secreted lactate induces M2-macrophage differentiation by metabolic reprogramming
- Source :
- Oncotarget
- Publication Year :
- 2016
- Publisher :
- Impact Journals LLC, 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 naive 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.
- Subjects :
- 0301 basic medicine
Stromal cell
Cellular differentiation
dendritic cell differentiation
Antigen presentation
Dendritic cell differentiation
Mice, SCID
Monocytes
Umbilical Cord
03 medical and health sciences
chemistry.chemical_compound
Lactate dehydrogenase
Medicine
Animals
Humans
Lactic Acid
Immune response
Interleukin 4
Cells, Cultured
lactate
business.industry
Gene Expression Profiling
Macrophages
Mesenchymal stem cell
Research Paper: Immunology
Immunity
Granulocyte-Macrophage Colony-Stimulating Factor
Cell Differentiation
Mesenchymal Stem Cells
Dendritic Cells
M2 Macrophage
Cell biology
Mice, Inbred C57BL
030104 developmental biology
Oncology
chemistry
Immunology
Immunology and Microbiology Section
M2-macrophages
Interleukin-4
business
mesenchymal stromal cells
metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 19492553
- Volume :
- 7
- Issue :
- 21
- Database :
- OpenAIRE
- Journal :
- Oncotarget
- Accession number :
- edsair.doi.dedup.....c4ce9acdc1d6f909d5478cd65b050abc