Murine endometrial-derived mesenchymal stem cells suppress experimental autoimmune encephalomyelitis depending on indoleamine-2,3-dioxygenase expression

Abstract

Cellular therapy with mesenchymal stem cells (MSCs) is a huge challenge for scientists, as little translational relevance has been achieved. However, many studies using MSCs have proved their suppressive and regenerative capacity. Thus, there is still a need for a better understanding of MSCs biology and the establishment of newer protocols, or to test unexplored tissue sources. Here, we demonstrate that murine endometrial-derived MSCs (meMSCs) suppress Experimental Autoimmune Encephalomyelitis (EAE). MSC-treated animals had milder disease, with a significant reduction in Th1 and Th17 lymphocytes in the lymph nodes and in the central nervous system (CNS). This was associated with increased Il27 and Cyp1a1 expression, and presence of IL-10-secreting T CD4+ cells. At EAE peak, animals had reduced CNS infiltrating cells, histopathology and demyelination. qPCR analysis evidenced the down-regulation of several pro-inflammatory genes and up-regulation of indoleamine-2,3-dioxygenase (IDO). Consistently, co-culturing of WT and IDO−/− meMSCs with T CD4+ cells evidenced the necessity of IDO on the suppression of encephalitogenic lymphocytes, and IDO−/− meMSCs were not able to suppress EAE. In addition, WT meMSCs stimulated with IL-17A and IFN-γ increased IDO expression and secretion of kynurenines in vitro, indicating a negative feedback loop. Pathogenic cytokines were increased when CD4+ T cells from AhR−/− mice were co-cultured with WT meMSC. In summary, our research evidences the suppressive activity of the unexplored meMSCs population, and shows the mechanism depends on IDO-kynurenines-Aryl hydrocarbon receptor (AhR) axis. To our knowledge this is the first report evidencing that the therapeutic potential of meMSCs relying on IDO expression.

Mesenchymal Stromal Cells: New Generation Treatment of Inflammatory Bowel Disease

“…143 It has been shown that IDO-depleted MSCs do not have the ability to modulate immune responses. 144 MSCs can also help to relieve inflammation by promoting the secretion of anti-inflammatory factors such as prostaglandin E2 (PGE2), TSG-6, and IL-10. 145 PGE2 promotes the production of Treg cells, enhances their activity and inhibits the activity of NKs and DC cells.…”

“… 143 It has been shown that IDO-depleted MSCs do not have the ability to modulate immune responses. 144 …”

Human Endometrial Regenerative Cells for Neurological Disorders: Hype or Hope?

“…Additionally, oleic acid increased the expression of ChAT and NF in hEnSCs, indicating hEnSCs have a great neuronal differentiation capacity (33). As shown in Table 1 (24,(35)(36)(37)(38)(39)(40)(41)(42)(43), The main characteristics of experimental research in the application of endometrial regenerative cells (ERCs) in some neurological models. PD: Parkinson's disease, hEnSCs: human endometrial derived stem cells, TH: tyrosine hydroxylase, MenSCs: menstrual blood-derived stem cells, MenSCs-CM: conditioned medium of human menstrual blood derived endometrial stem cells, ROS: reactive oxygen species, OGD: oxygen glucose deprivation, VEGF: vascular endothelial growth factor, BDNF: brain-derived neurotrophic factor, NT3: neurotrophin-3, SCI: spinal cord injury, EVs: extracellular vesicles.…”

Re-establishing immune tolerance in multiple sclerosis: focusing on novel mechanisms of mesenchymal stem cell regulation of Th17/Treg balance

“…In contrast, MSCs enhance the immunosuppressive ability of Tregs. For instance, MSCs induce FoxP3 expression by secreting indoleamine 2, 3-dioxygenase (IDO), which increases the proportion of Tregs in the spleen of EAE patients, leading to a reduction in the clinical score and severity of EAE [ 84 ]. Meanwhile, in vitro experiments have shown that co-culture of T cells and MSCs can significantly upregulate FoxP3 expression in Tregs and increase the proportion of Tregs [ 85 ].…”

“…Therefore, IL-37 is a promising novel target for future MS therapies. Other soluble factors such as IDO [ 84 , 96 ], TGF-β [ 97 ], prostaglandin E2 (PGE2) [ 98 ], hepatocyte growth factor [ 99 ], human leukocyte antigen (HLA)-G5 [ 100 ], heme oxygenase-1 [ 101 ], and inducible nitric oxide synthase may also be involved in the regulation of Th17/Treg homeostasis. Table 1 summarizes the major soluble factors that regulate Th17/Treg homeostasis in MSCs.…”