Human mesenchymal stromal cell-secreted lactate induces M2-macrophage differentiation by metabolic reprogramming

// 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 , Renee 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 Beausejour 1,4 , David Stroncek 3 , Francoise 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, Hema-Quebec, Quebec, 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 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.