title: Human mesenchymal stromal cell-secreted lactate induces M2-macrophage differentiation by metabolic reprogramming.
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.
authors.affiliation: CHU Sainte-Justine Research Center, Montreal, QC, Canada.|Department of Microbiology, Infectiology and Immunology, University of Montreal, Montreal, QC, Canada.
authors.forename: Silvia
authors.initials: S
authors.lastname: Selleri
authors.affiliation: CHU Sainte-Justine Research Center, Montreal, QC, Canada.|Department of Microbiology, Infectiology and Immunology, University of Montreal, Montreal, QC, Canada.
authors.forename: Panojot
authors.initials: P
authors.lastname: Bifsha
authors.affiliation: Department of Transfusion Medicine, Clinical Center, NIH, Bethesda, MD, USA.
authors.forename: Sara
authors.initials: S
authors.lastname: Civini
authors.affiliation: Department of Pharmacology, University of Montreal, Montreal, QC, Canada.
authors.forename: Consiglia
authors.initials: C
authors.lastname: Pacelli
authors.affiliation: CHU Sainte-Justine Research Center, Montreal, QC, Canada.|Department of Biology, New York University, Abu Dhabi, United Arab Emirates.
authors.forename: Mame Massar
authors.initials: MM
authors.lastname: Dieng
authors.affiliation: CHU Sainte-Justine Research Center, Montreal, QC, Canada.|Department of Microbiology, Infectiology and Immunology, University of Montreal, Montreal, QC, Canada.
authors.forename: William
authors.initials: W
authors.lastname: Lemieux
authors.affiliation: Department of Transfusion Medicine, Clinical Center, NIH, Bethesda, MD, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Jin
authors.affiliation: Department of Research and Development, Héma-Québec, Québec, QC, Canada.
authors.forename: Renée
authors.initials: R
authors.lastname: Bazin
authors.affiliation: Department of Pathology, University of Montreal, Montreal, QC, Canada.
authors.forename: Natacha
authors.initials: N
authors.lastname: Patey
authors.affiliation: Department of Transfusion Medicine, Clinical Center, NIH, Bethesda, MD, USA.|Sidra Medical and Research Center, Doha, Qatar.
authors.forename: Francesco M
authors.initials: FM
authors.lastname: Marincola
authors.affiliation: CHU Sainte-Justine Research Center, Montreal, QC, Canada.|Faculty of Dentistry, University of Montreal, Montreal, QC, Canada.
authors.forename: Florina
authors.initials: F
authors.lastname: Moldovan
authors.affiliation: CHU Sainte-Justine Research Center, Montreal, QC, Canada.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Zaouter
authors.affiliation: Department of Pharmacology, University of Montreal, Montreal, QC, Canada.
authors.forename: Louis-Eric
authors.initials: LE
authors.lastname: Trudeau
authors.affiliation: CHU Sainte-Justine Research Center, Montreal, QC, Canada.
authors.forename: Basma
authors.initials: B
authors.lastname: Benabdhalla
authors.affiliation: CHU Sainte-Justine Research Center, Montreal, QC, Canada.|Department of Pediatrics, University of Montreal, Montreal, QC, Canada.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Louis
authors.affiliation: CHU Sainte-Justine Research Center, Montreal, QC, Canada.|Department of Pharmacology, University of Montreal, Montreal, QC, Canada.
authors.forename: Christian
authors.initials: C
authors.lastname: Beauséjour
authors.affiliation: Department of Transfusion Medicine, Clinical Center, NIH, Bethesda, MD, USA.
authors.forename: David
authors.initials: D
authors.lastname: Stroncek
authors.affiliation: CHU Sainte-Justine Research Center, Montreal, QC, Canada.|Department of Microbiology, Infectiology and Immunology, University of Montreal, Montreal, QC, Canada.|Department of Pediatrics, University of Montreal, Montreal, QC, Canada.
authors.forename: Françoise
authors.initials: F
authors.lastname: Le Deist
authors.affiliation: CHU Sainte-Justine Research Center, Montreal, QC, Canada.|Department of Microbiology, Infectiology and Immunology, University of Montreal, Montreal, QC, Canada.|Department of Pediatrics, University of Montreal, Montreal, QC, Canada.
authors.forename: Elie
authors.initials: E
authors.lastname: Haddad
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics*; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology / Q000378:metabolism; D020869:Gene Expression Profiling / Q000379:methods; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D015847:Interleukin-4 / Q000494:pharmacology; D019344:Lactic Acid / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D009000:Monocytes / Q000166:cytology / Q000378:metabolism; D014470:Umbilical Cord / Q000166:cytology
chemical_list: D015847:Interleukin-4; D019344:Lactic Acid; D016178:Granulocyte-Macrophage Colony-Stimulating Factor
keywords: Immune response; Immunity; Immunology and Microbiology Section; M2-macrophages; dendritic cell differentiation; lactate; mesenchymal stromal cells; metabolism