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.

Local Treatment with Lactate Prevents Intestinal Inflammation in the TNBS-Induced Colitis Model

“…We have recently shown that lactate impairs macrophage metabolic reprograming after LPS activation in a GPR81-independent manner (22), which has also been associated with blunting the proinflammatory cytokine response (46). In accordance with these results, Selleri et al (47) have shown that local increase of lactate in the environment of mesenchymal stromal cells shifts macrophage M1 activation toward the less inflammatory M2 (47). Colegio et al (48) have shown also the blunting of M1 macrophage activation in the solid tumor environment due to high lactate production of Warburg metabolism of tumor cells (48).…”

Lactate secreted by cervical cancer cells modulates macrophage phenotype

“…12,13 Besides, tumor cell metabolites may also control M phenotype. Selleri and co-workers showed that lactate, secreted by mesenchymal stromal cells, skewed GM-CSF/IL-4 driven dendritic cells maturation from monocytes to M2 M s. 14 In a similar fashion, Colegio and co-workers showed that lactate can promote M2 M phenotype through hypoxia induced factor-1 (HIF-1 ) stabilization. 15 Indeed, lactate may be secreted at high concentration by tumor cells, due to their metabolic status.…”

The influence of macrophages on mesenchymal stromal cell therapy: passive or aggressive agents?

“…An array of studies have demonstrated the capacity for MSC to modulate inflammatory M1 macrophages and promote anti-inflammatory M2 macrophages [15,37,40]. The recent progress made in the field of immunometabolism has been reflected in the MSC field, with Selleri et al [39] reporting the capacity of umbilical cord MSC (UC-MSC) to promote an M2 phenotype in a lactate-dependent manner. The M2 gene expression signature was confirmed by expression of typical macrophage and M2 gene transcripts such as CD14, CD16, CD68 and IL-10.…”