Restrained Th17 response and myeloid cell infiltration into the central nervous system by human decidua-derived mesenchymal stem cells during experimental autoimmune encephalomyelitis

Abstract

BackgroundMultiple sclerosis is a widespread inflammatory demyelinating disease. Several immunomodulatory therapies are available, including interferon-β, glatiramer acetate, natalizumab, fingolimod, and mitoxantrone. Although useful to delay disease progression, they do not provide a definitive cure and are associated with some undesirable side-effects. Accordingly, the search for new therapeutic methods constitutes an active investigation field. The use of mesenchymal stem cells (MSCs) to modify the disease course is currently the subject of intense interest. Decidua-derived MSCs (DMSCs) are a cell population obtained from human placental extraembryonic membranes able to differentiate into the three germ layers. This study explores the therapeutic potential of DMSCs.MethodsWe used the experimental autoimmune encephalomyelitis (EAE) animal model to evaluate the effect of DMSCs on clinical signs of the disease and on the presence of inflammatory infiltrates in the central nervous system. We also compared the inflammatory profile of spleen T cells from DMSC-treated mice with that of EAE control animals, and the influence of DMSCs on the in vitro definition of the Th17 phenotype. Furthermore, we analyzed the effects on the presence of some critical cell types in central nervous system infiltrates.ResultsPreventive intraperitoneal injection of DMSCs resulted in a significant delay of external signs of EAE. In addition, treatment of animals already presenting with moderate symptoms resulted in mild EAE with reduced disease scores. Besides decreased inflammatory infiltration, diminished percentages of CD4+IL17+, CD11b+Ly6G+ and CD11b+Ly6C+ cells were found in infiltrates of treated animals. Early immune response was mitigated, with spleen cells of DMSC-treated mice displaying low proliferative response to antigen, decreased production of interleukin (IL)-17, and increased production of the anti-inflammatory cytokines IL-4 and IL-10. Moreover, lower RORγT and higher GATA-3 expression levels were detected in DMSC-treated mice. DMSCs also showed a detrimental influence on the in vitro definition of the Th17 phenotype.ConclusionsDMSCs modulated the clinical course of EAE, modified the frequency and cell composition of the central nervous system infiltrates during the disease, and mediated an impairment of Th17 phenotype establishment in favor of the Th2 subtype. These results suggest that DMSCs might provide a new cell-based therapy for the control of multiple sclerosis.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-016-0304-5) contains supplementary material, which is available to authorized users.

Concise Review: Mesenchymal Stem Cells in Neurodegenerative Diseases

“…Using hBM‐MSCs, Bai et al showed a decrease in leukocyte infiltration into the CNS and enhanced a Th2 cytokine profile, but also enhanced oligodendrogenesis, suggesting that hBM‐MSCs affect immunomodulation but also enhanced neuronal repair . Similar results showing a Th2 cytokine shift and enhanced oligodendrogenesis were reported using hA‐MSCs and using human decidua‐derived MSCs (hD‐MSCs) . hA‐MSCs were also shown to express the immunosuppressive gene human leukocyte antigen G (HLA‐G) and to induce the secretion of the anti‐inflammatory protein TNF‐α‐stimulated gene/protein 6 following culture with inflammatory cytokines .…”

The transplantation of mesenchymal stem cells derived from unconventional sources: an innovative approach to multiple sclerosis therapy

“…Delay of the disease onset and reduction of the disability score Bravo et al (2016) in a Chinese population . In detail, on day 0, eight enrolled patients received an intravenous injection of 2 × 10 7 hUC-MSCs followed by an intrathecal injection at the same dose.…”

“…In a recent study conducted in 2016, Bravo et al (2016) used the EAE model in order to evaluate the therapeutic effects of human decidua-derived MSCs (DD-MSCs). DD-MSCs are a cell population obtained from placental extraembryonic membranes and with a proliferation rate and capacity to differentiation higher than BM-MSCs.…”

Immunomodulatory Effects of Mesenchymal Stem Cells on T- and B-Cells in a Quiescent State in a Chronic Experimental Model of Autoimmune Encephalomyelitis

“…A potential alternative to neural precursor cells is mesenchymal stem cells (MSC). Recently, the actions exerted by adipose-derived mesenchymal stromal cells, [10][11][12][13][14] placenta-derived mesenchymal stem cells, 15,16 Wharton's jelly mesenchymal stem cells, 17 human decidua-derived mesenchymal stem cells 18 and human umbilical cord blood mesenchymal stromal cells 19 have been reported in experimental autoimmune encephalomyelitis (EAE) animal models.…”

“…These cells could be ideal candidates for application in human diseases, since they offer significant practical advantages: they are obtained from different adult tissues and can readily be cultured and expanded; they are multipotent and self-renewing. They have the capacity to differentiate into mesodermal-derived 20 or into neural-like and glial-like cells 21 ; they have been shown to have immunoregulatory properties 10,[12][13][14]17,18,22,23 ; they secrete factors that may stimulate endogenous neural stem cells in the CNS 24,25 ; they can be safely injected autologously without the need for immunosuppression 26 ; they decrease the number of infiltrating inflammatory cells, preserving axons and ameliorating demyelination, 15,19,27,28 ameliorate neuroinflammation 11,29 and exert a neurotrophic action. 16 All these features make MSC suitable for therapy in autoimmune diseases.…”