• Clinical trials
• Heterogeneity
• Mesenchymal stem cells
• Systemic lupus erythematosus

• Humans
• Lupus Erythematosus, Systemic/therapy
• Lupus Erythematosus, Systemic/pathology
• Lupus Erythematosus, Systemic/immunology
• Mesenchymal Stem Cells/cytology
• Mesenchymal Stem Cell Transplantation/methods
• Cell Differentiation
• Animals

• Cell culture
• Confluency
• Graft-versus-host disease
• Immunomodulation
• Mesenchymal stromal cells
• T cells

• Animals
• Mice
• Humans
• Leukocytes, Mononuclear
• Bone Marrow
• Phosphatidylinositol 3-Kinases
• Mesenchymal Stem Cells
• Cytokines
• Disease Models, Animal
• DNA-Binding Proteins
• Transcription Factors
• Intercellular Signaling Peptides and Proteins

• National Research Foundation Singapore
• Biomedical Research Council
• Massachusetts Institute of Technology (MIT)

• Arthritis
• Mesenchymal stem cell
• T lymphocytes

• Humans
• Cytokines
• Interleukin-9
• Interleukin-17
• Autoimmune Diseases
• Mesenchymal Stem Cells
• Arthritis

• Autoimmune activation
• Mathematical modeling
• Mesenchymal stem cells
• Systemic inflammation
• Systemic lupus erythematosus (SLE)
• Tolerance breach

• CD4+T cells
• Colitis-associated colon cancer
• Immunomodulatory
• Mesenchymal stem cells

• 82170571 National Natural Science Foundation of China
• 81974068 National Natural Science Foundation of China
• 81900580 National Natural Science Foundation of China
• 82270586 National Natural Science Foundation of China
• 2022CFA009 Natural Science Foundation of Hubei Province

• Autoimmune diseases
• Immunomodulation
• Mesenchymal stem cells
• Pristane
• Systemic lupus erythematosus
• T helper cell

• antibody mediated rejection
• kidney allograft
• kidney transplant
• mesenchymal stem cells
• stem cells

• Autoimmunity
• B-Lymphocytes
• Lupus Erythematosus, Systemic

• Female
• Humans
• Lupus Erythematosus, Systemic/drug therapy
• Mesenchymal Stem Cell Transplantation/adverse effects
• Mesenchymal Stem Cells
• Transforming Growth Factor beta
• Umbilical Cord

• R01 DK118529 NIDDK NIH HHS
• R01 DK120394 NIDDK NIH HHS
• R01 DK126454 NIDDK NIH HHS
• UL1 RR029882 NCRR NIH HHS
• NIGMS
• Lupus Foundation of America

• T lymphocytes
• immunosuppression
• intercellular adhesion molecule-1
• interferon γ
• periodontal ligament cells
• transforming growth factor β1

• Thailand Science Research and Innovation

• CTLA-4
• PD-1
• PD-L1
• emerging immune checkpoints
• immune checkpoint inhibitors
• immunological effects
• immunotherapy
• metastatic melanoma
• tumor microenvironment

• MSC
• Mesenchymal stem cells
• cancer cells
• genetically engineered MSCs
• therapeutic
• tissue repairing

• Adipose
• Allogenic
• Bone Marrow
• Immunomodulation
• Mesenchymal Stem Cells

• T helper cell subsets
• adipose-derived mesenchymal stem cells
• ankylosing spondylitis
• cytokines
• transcription factors

• Adipose Tissue/metabolism
• Cell Differentiation
• Female
• Humans
• Male
• Mesenchymal Stem Cells/metabolism
• Spondylitis, Ankylosing/genetics
• Spondylitis, Ankylosing/pathology
• Th1 Cells/metabolism

Mesenchymal stromal cells (MSC) exert their immunomodulatory potential on several cell types of the immune system, affecting and influencing the immune response. MSC efficiently inhibit T cell proliferation, reduce the secretion of pro-inflammatory cytokines, limit the differentiation of pro-inflammatory Th subtypes and promote the induction of regulatory T cells (Treg). In this study, we analyzed the immunomodulatory potential of human adipose tissue-derived MSC (ASC), on CD4+ T cells, addressing potential cell-contact dependency in relation to T cell receptor stimulation of whole human peripheral blood mononuclear cells (PBMC). ASC were cultured with not stimulated or anti-CD3/CD28-stimulated PBMC in direct and transwell cocultures; PBMC alone were used as controls. After 7 days, cocultures were harvested and we analyzed: (1) the inhibitory potential of ASC on CD4+ cell proliferation and (2) phenotypic changes in CD4+ cells in respect of Treg marker (CD25, CD127 and FoxP3) expression. We confirmed the inhibitory potential of ASC on CD4+ cell proliferation, which occurs upon PBMC stimulation and is mediated by indoleamine 2,3-dioxygenase. Importantly, ASC reduce both pro- and anti-inflammatory cytokine secretion, without indications on specific Th differentiation. We found that stimulation induces CD25 expression on CD4+ cells and that, despite inhibiting overall CD4+ cell proliferation, ASC can specifically induce the proliferation of CD4+CD25+ cells. We observed that ASC induce Treg (CD4+CD25+CD127−FoxP3+) only in not stimulated cocultures and that ASC increase the ratio of CD4+CD25+CD127+FoxP3− cells at the expense of CD4+CD25+CD127−FoxP3− cells. Our study provides new insights on the interplay between ASC and CD4+ T cells, proposing that ASC-dependent induction of Treg depends on PBMC activation which affects the balance between the different subpopulations of CD4+CD25+ cells expressing CD127 and/or FoxP3.

• CD127
• CD4 T cells
• immunomodulation
• mesenchymal stromal cells
• regulatory T cells

Recent evidence has shown that CD4⁺ T helper (Th) cells are involved in renal inflammation and fibrosis. However, whether renal fibrosis can be alleviated by intervening in the polarization of CD4⁺ T cells remains unknown. Our research investigated the effects of intravenously administered placenta mesenchymal stromal cells (PMSCs) or treatment with extracellular EVs (EVs) derived from PMSCs (PMSC-EVs) on the polarization of CD4⁺ T cells in rats with unilateral ureteral obstruction (UUO). We further verified how PMSCs affect inflammatory factor secretion and the levels of regulatory T (Treg) and Th17 CD4⁺ T cells in vitro.

We evaluated renal interstitial inflammation and fibrosis by pathological section staining, tested the polarization of CD4⁺ T cells (Th17 and Treg phenotypes) by flow cytometry (FCM) and immunohistochemistry, and detected the cytokines secreted by CD4⁺ T cells by enzyme-linked immunosorbent assay (ELISA).

Compared with that of control rats, the renal tissue of PMSC-treated rats exhibited lower renal Masson scores and more Foxp3⁺ cell infiltration, with a significantly decreased IL17A⁺CD4⁺ T cell/CD4⁺ T cell ratio and a significantly elevated anti-inflammatory cytokine (IL-10) level. When CD4⁺ T cells were cocultured with PMSCs, CD4⁺IL17A⁺ cell percentages were decreased in a UUO model after 7 days of coculture with PMSCs. The secretion of TGF-β and IL-10 was significantly increased (P < 0.05), while the secretion of IFN-γ, IL-17, and IL-6 was significantly decreased (P < 0.05) in the PMSC coculture group. Moreover, after treatment with PMSC-EVs, tubulointerstitial fibrosis was alleviated, and Foxp3⁺/IL-17⁺ cell infiltration was increased in the kidneys of UUO model animals on day 7.

PMSCs can convert the inflammatory environment into an anti-inflammatory environment by affecting the polarization of CD4⁺ T cells and macrophages, inhibiting the inflammatory factors IFN-γ and IL-17, and upregulating the expression of the anti-inflammatory factors TGF-β and IL-10, ultimately leading to renal protection. Such functions may be mediated by the paracrine activity of PMSC-EVs.

• Immune tolerance
• Immunomodulation
• Kidney transplantation
• Mesenchymal stem cells
• Mesenchymal stromal cells
• Regulatory T-cells
• T-lymphocytes

• cytokines
• immunosuppression
• lymphocytes
• stem cells

To investigate the therapeutic effect of intercellular adhesion molecule (ICAM)-1-modified mesenchymal stem cells (MSCs) in a mouse model of inflammatory bowel disease (IBD) induced by dextran sulfate sodium.

Primary MSCs and ICAM-1-overexpressing MSCs (C3 cells) were generated in vitro. The IBD mouse model was induced with drinking water containing dextran sulfate sodium for 7 days. For stem cell therapy, mice were randomly assigned to six experimental groups: the control group, IBD group, primary MSC group, C3 group, C3-vector group, and C3-ICAM-1 group. Mice were given a single injection of 1 × 10⁶ primary MSCs or gene-modified MSCs via the tail vein on day 3 of DDS administration. The general conditions of the mice in each group were observed. Additionally, the pathological changes in the colon were observed and scored. Primary MSCs and gene-modified MSCs were stained with the fluorescent dye CM-DIL before injection into the tail vein of mice. The distribution of infused cells in IBD mice was observed in frozen sections. Mechanistically, the polarization of Th1, Th2, Th17, and regulatory T cells (Tregs) in the spleen was determined by flow cytometry. Moreover, the mRNA expression levels of IBD-related immune factors in splenocytes were measured by quantitative PCR.

A single injection of MSCs promoted general recovery and reduced pathological damage in IBD mice. Additionally, ICAM-1-overexpressing MSCs had stronger therapeutic effects than ICAM-1^low MSCs. Furthermore, the in vivo distribution analysis results indicated that a higher number of ICAM-1-overexpressing MSCs homed to the colon and spleen of IBD mice. Moreover, the delivery of ICAM-1 overexpressing MSCs decreased the numbers of Th1 and Th17 cells but increased the number of Tregs in the spleen of IBD mice. The quantitative PCR analysis results revealed that an infusion of ICAM-1-overexpressing MSCs influenced the expression of spleen-derived immune factors by remarkably reducing the mRNA levels of IFN-γ and IL-17A and increasing the mRNA level of Foxp3.

Our results demonstrate that ICAM-1-modified mesenchymal stem cells (MSCs) remarkably alleviate inflammatory damage in IBD mice by promoting MSC homing to the target and immune organs. The findings suggest that ICAM-1 is required to maintain the therapeutic effects of MSCs in IBD treatment and identified a novel role of ICAM-1 in inflammatory diseases.

The online version of this article (10.1186/s13287-019-1384-9) contains supplementary material, which is available to authorized users.

• Homing
• Inflammatory bowel disease
• Intercellular cell adhesion molecule-1
• Mesenchymal stem cells

In solid organ transplantation lifelong immunosuppression exposes transplant recipients to life-threatening complications, such as infections and malignancies, and to severe side effects. Cellular therapy with mesenchymal stromal cells (MSC) has recently emerged as a promising strategy to regulate anti-donor immune responses, allowing immunosuppressive drug minimization and tolerance induction. In this review we summarize preclinical data on MSC in solid organ transplant models, focusing on potential mechanisms of action of MSC, including down-regulation of effector T-cell response and activation of regulatory pathways. We will also provide an overview of available data on safety and feasibility of MSC therapy in solid organ transplant patients, highlighting the issues that still need to be addressed before establishing MSC as a safe and effective tolerogenic cell therapy in transplantation.

• B cells
• T cells
• macrophage
• mesenchymal (stromal) stem cells
• tolerance
• transplantation

• Mesenchymal stem cells
• adaptive immune response
• immunomodulation
• innate immune response
• metastasis
• tumor microenvironment.

• Adaptive Immunity/physiology
• Apoptosis
• Cancer-Associated Fibroblasts/metabolism
• Epithelial-Mesenchymal Transition/physiology
• Humans
• Immunity, Innate/physiology
• Mesenchymal Stem Cells/physiology
• Neoplasms/immunology
• Neoplasms/metabolism
• Neoplastic Stem Cells/physiology
• Tumor Microenvironment/physiology

Tertiary lymphoid structures (TLS) develop in the kidneys of lupus-prone mice and systemic lupus erythematosus (SLE) patients with lupus nephritis (LN). Here we investigated the presence of mesenchymal stem cells (MSCs) in the development of TLS in murine LN, as well as the role of human MSCs as lymphoid tissue organizer (LTo) cells on the activation of CD4+ T cells from three groups of donors including Healthy, SLE and LN patients. Mesenchymal stem like cells were detected within the pelvic wall and TLS in kidneys of lupus-prone mice. An increase in LTβ, CXCL13, CCL19, VCAM1 and ICAM1 gene expressions were detected during the development of murine LN. Human MSCs stimulated with the pro-inflammatory cytokines TNF-α and IL-1β significantly increased the expression of CCL19, VCAM1, ICAM1, TNF-α, and IL-1β. Stimulated MSCs induced proliferation of CD4⁺ T cells, but an inhibitory effect was observed when in co-culture with non-stimulated MSCs. A contact dependent increase in Th2 and Th17 subsets were observed for T cells from the Healthy group after co-culture with stimulated MSCs. Our data suggest that tissue-specific or/and migratory MSCs could have pivotal roles as LTo cells in accelerating early inflammatory processes and initiating the formation of kidney specific TLS in chronic inflammatory conditions.

Since being discovered over half a century ago, mesenchymal stem cells (MSCs) have been investigated extensively to characterize their cellular and physiological influences. MSCs have been shown to possess immunosuppressive capacity through inhibiting lymphocyte activation/proliferation and proinflammatory cytokine secretion while simultaneously demonstrating limited allogenic reactivity, which subsequently led to the evaluation of therapeutic feasibility to treat inflammatory diseases. Although regulatory constraints have restricted MSC development pharmacologically, limited clinical studies have shown encouraging results using MSC infusions to treat systemic lupus erythematosus (SLE); but, more trials will have to be performed to conclusively determine the clinical efficacy of MSCs to treat SLE. Moreover, there are some data to suggest that MSCs possess tumorigenic potential and that the immunosuppressive influence can be dramatically affected by both donor variability and ex vivo expansion. Given that recent studies have found that the immunosuppressive effects of MSCs are a result, at least in part, to extracellular vesicle (EV) secretion, the use of MSC-derived EVs has been suggested as a cell-free therapeutic alternative. Despite the positive data observed using EVs isolated from human MSCs to suppress inflammatory responses in vitro and in inhibiting autoimmune disease pathogenesis in preclinical work, there are no studies to date examining EVs from MSCs to treat SLE in humans or animal models. Considering that EVs are not subject to the strict regulatory constraints of stem cell-based pharmacological development and are more readily standardized with regard to industrial-scale production and storage, this review outlines the anti-inflammatory biology of MSCs and the scientific evidence supporting the potential use of EVs derived from human MSCs to treat patients with SLE.

• autoimmunity
• emerging therapies
• extracellular vesicles
• inflammation
• mesenchymal stem cells
• systemic lupus erythematosus

Inflammatory skin disorders that cause serious deterioration of the quality of life have become one of the major public concerns. Despite their significance, there is no fundamental cure to date. Mesenchymal stem cells (MSCs) possess unique immunomodulatory properties which make them a promising tool for the treatment of various inflammatory diseases. Our recent preclinical and clinical studies have shown that MSCs can be successfully used for the treatment of atopic dermatitis (AD), one of the major inflammatory skin diseases. This observation along with similar reports from other groups revealed the efficacy and underlying mechanisms of MSCs in inflammatory dermatosis. In addition, it has been proposed that cell priming or gene transduction can be novel strategies for the development of next-generation high-efficacy MSCs for treating inflammatory skin diseases. We discuss here existing evidence that demonstrates the regulatory properties of MSCs on immune responses under inflammatory conditions.

• atopic dermatitis
• immunomodulation
• inflammatory skin diseases
• mesenchymal stem cells
• psoriasis
• stem cell therapy

• cell therapy
• dextran sulfate sodium–induced colitis
• immunosuppression
• inflammatory bowel disease
• toll-like receptors
• umbilical cord–derived mesenchymal stromal cells

Recently, it has been observed that mesenchymal stem cells (MSCs) can modulate their immunoregulatory properties depending on the specific in-vitro activation of different Toll-like receptors (TLR), such as TLR3 and TLR4. In the present study, we evaluated the effect of polyinosinic:polycytidylic acid (poly(I:C)) and lipopolysaccharide (LPS) pretreatment on the immunological capacity of MSCs in vitro and in vivo.

C57BL/6 bone marrow-derived MSCs were pretreated with poly(I:C) and LPS for 1 hour and their immunomodulatory capacity was evaluated. T-cell proliferation and their effect on Th1, Th17, and Treg differentiation/activation were measured. Next, we evaluated the therapeutic effect of MSCs in an experimental autoimmune encephalomyelitis (EAE) model, which was induced for 27 days with MOG_35–55 peptide following the standard protocol. Mice were subjected to a single intraperitoneal injection (2 × 10⁶ MSCs/100 μl) on day 4. Clinical score and body weight were monitored daily by blinded analysis. At day 27, mice were euthanized and draining lymph nodes were extracted for Th1, Th17, and Treg detection by flow cytometry.

Pretreatment of MSCs with poly(I:C) significantly reduced the proliferation of CD3⁺ T cells as well as nitric oxide secretion, an important immunosuppressive factor. Furthermore, MSCs treated with poly(I:C) reduced the differentiation/activation of proinflammatory lymphocytes, Th1 and Th17. In contrast, MSCs pretreated with LPS increased CD3⁺ T-cell proliferation, and induced Th1 and Th17 cells, as well as the levels of proinflammatory cytokine IL-6. Finally, we observed that intraperitoneal administration of MSCs pretreated with poly(I:C) significantly reduced the severity of EAE as well as the percentages of Th1 and Th17 proinflammatory subsets, while the pretreatment of MSCs with LPS completely reversed the therapeutic immunosuppressive effect of MSCs.

Taken together, these data show that pretreatment of MSCs with poly(I:C) improved their immunosuppressive abilities. This may provide an opportunity to better define strategies for cell-based therapies to autoimmune diseases.

• Autoimmunity
• Experimental autoimmune encephalomyelitis
• Immunomodulation
• Mesenchymal stem cells
• Toll-like receptors 3 and 4

• Autoimmunity
• Immunomodulation
• Mesenchymal stem cells
• Regulatory B cells
• Regulatory T cells

• CD(4) T cell
• FoxP3
• Gata3
• Hepatocyte growth factor
• Immunomodulation
• Interleukin
• Mesenchymal stem cell
• Stat3
• T-bet

• Bone regeneration
• Fracture healing
• Mesenchymal stem cell
• Osteoimmunology
• T lymphocytes

• Aged
• CD4-Positive T-Lymphocytes/cytology
• CD4-Positive T-Lymphocytes/drug effects
• Cell Differentiation/drug effects
• Cell Proliferation/drug effects
• Culture Media, Conditioned/pharmacology
• Female
• Humans
• Inflammation Mediators/metabolism
• Interleukin-17/pharmacology
• Lymphocyte Activation/drug effects
• Lymphocyte Activation/immunology
• Lymphocyte Subsets/cytology
• Lymphocyte Subsets/drug effects
• Male
• Mesenchymal Stem Cells/cytology
• Mesenchymal Stem Cells/drug effects
• Mesenchymal Stem Cells/metabolism
• Middle Aged
• Osteoblasts/cytology
• Osteoblasts/drug effects
• Osteoblasts/metabolism
• Osteogenesis/drug effects

Mesenchymal stromal cells (MSC) have gained immense attraction in regenerative medicine, tissue engineering, and immunotherapy. This is based on their differentiation potential and the supply of pro-regenerative and immunomodulatory signals. MSC can be isolated from a multitude of tissue sources, but mainly bone marrow, adipose tissue, and birth-associated tissues (e.g., umbilical cord, cord blood, placenta) appear to be relevant for clinical translation in immune-mediated disorders. However, only a few studies directly compared the immunomodulatory potency of MSC from different tissue sources. This review compiles the current literature regarding the similarities and differences between these three sources for MSCs with a special focus on their immunomodulatory effects on T-lymphocyte subsets and monocytes, macrophages, and dendritic cells.

• T cells
• adipose tissue
• bone marrow
• immunomodulation
• macrophages
• mesenchymal stromal cells
• regulatory T cells
• umbilical cord

Ischemia/reperfusion injury (IRI) represents a worldwide public health issue of increasing incidence. IRI may virtually affect all organs and tissues and is associated with significant morbidity and mortality. Particularly, the duration of blood supply deprivation has been recognized as a critical factor in stroke, hemorrhagic shock, or myocardial infarction, as well as in solid organ transplantation (SOT). Pathophysiologically, IRI causes multiple cellular and tissular metabolic and architectural changes. Furthermore, the reperfusion of ischemic tissues induces both local and systemic inflammation. In the particular field of SOT, IRI is an unavoidable event, which conditions both short- and long-term outcomes of graft function and survival. Clinically, the treatment of patients with IRI mostly relies on supportive maneuvers since no specific target-oriented therapy has been validated thus far. In the present review, we summarize the current literature on mesenchymal stromal cells (MSC) and their potential use as cell therapy in IRI. MSC have demonstrated immunomodulatory, anti-inflammatory, and tissue repair properties in rodent studies and in preliminary clinical trials, which may open novel avenues in the management of IRI and SOT.

• Adaptive immune responses
• Immunoregulation
• Mesenchymal stem cells
• Plasticity

The immunosuppressive properties of mesenchymal stromal/stem cells (MSC) rendered them an attractive therapeutic approach for immune disorders and an increasing body of evidence demonstrated their clinical value. However, the influence of MSC on the function of specific immune cell populations, namely, monocyte subpopulations, is not well elucidated. Here, we investigated the influence of human bone marrow MSC on the cytokine and chemokine expression by peripheral blood classical, intermediate and nonclassical monocytes, and myeloid dendritic cells (mDC), stimulated with lipopolysaccharide plus interferon (IFN)γ. We found that MSC effectively inhibit tumor necrosis factor- (TNF-) α and macrophage inflammatory protein- (MIP-) 1β protein expression in monocytes and mDC, without suppressing CCR7 and CD83 protein expression. Interestingly, mDC exhibited the highest degree of inhibition, for both TNF-α and MIP-1β, whereas the reduction of TNF-α expression was less marked for nonclassical monocytes. Similarly, MSC decreased mRNA levels of interleukin- (IL-) 1β and IL-6 in classical monocytes, CCL3, CCL5, CXCL9, and CXCL10 in classical and nonclassical monocytes, and IL-1β and CXCL10 in mDC. MSC do not impair the expression of maturation markers in monocytes and mDC under our experimental conditions; nevertheless, they hamper the proinflammatory function of monocytes and mDC, which may impede the development of inflammatory immune responses.

• Adult Stem Cells/immunology
• Animals
• Cell Lineage/immunology
• Cell Proliferation
• Humans
• Immunomodulation/immunology
• Immunosuppression Therapy
• Mesenchymal Stem Cells/immunology
• Multipotent Stem Cells/immunology
• Periodontal Ligament/cytology
• Regeneration/immunology
• T-Lymphocytes/immunology
• Transplantation Immunology

• mscs
• myeloma
• immunomodulation
• th17/treg

• CD40 Antigens/metabolism
• Coculture Techniques
• Cytokines/metabolism
• Humans
• Immunomodulation
• Inflammation/immunology
• Inflammation/metabolism
• Inflammation Mediators/metabolism
• Lymphocyte Activation/immunology
• Lymphocyte Count
• Mesenchymal Stem Cells/immunology
• Mesenchymal Stem Cells/metabolism
• Multiple Myeloma/immunology
• Multiple Myeloma/metabolism
• T-Lymphocyte Subsets/immunology
• T-Lymphocyte Subsets/metabolism
• T-Lymphocytes, Regulatory/immunology
• T-Lymphocytes, Regulatory/metabolism
• Th17 Cells/immunology
• Th17 Cells/metabolism
• Vascular Cell Adhesion Molecule-1/metabolism

The different distribution of T cells among activation/differentiation stages in immune disorders may condition the outcome of mesenchymal stromal cell (MSC)-based therapies. Indeed, the effect of MSCs in the different functional compartments of T cells is not completely elucidated.

We investigated the effect of human bone marrow MSCs on naturally occurring peripheral blood functional compartments of CD4⁺ and CD8⁺ T cells: naive, central memory, effector memory, and effector compartments. For that, mononuclear cells (MNCs) stimulated with phorbol myristate acetate (PMA) plus ionomycin were cultured in the absence/presence of MSCs. The percentage of cells expressing tumor necrosis factor-alpha (TNF-α), interferon gamma (IFNγ), and interleukin-2 (IL-2), IL-17, IL-9, and IL-6 and the amount of cytokine produced were assessed by flow cytometry. mRNA levels of IL-4, IL-10, transforming growth factor-beta (TGF-β), and cytotoxic T-lymphocyte-associated protein 4 (CTLA4) in purified CD4⁺ and CD8⁺ T cells, and phenotypic and mRNA expression changes induced by PMA + ionomycin stimulation in MSCs, were also evaluated.

MSCs induced the reduction of the percentage of CD4⁺ and CD8⁺ T cells producing TNF-α, IFNγ, and IL-2 in all functional compartments, except for naive IFNγ⁺CD4⁺ T cells. This inhibitory effect differentially affected CD4⁺ and CD8⁺ T cells as well as the T-cell functional compartments; remarkably, different cytokines showed distinct patterns of inhibition regarding both the percentage of producing cells and the amount of cytokine produced. Likewise, the percentages of IL-17⁺, IL-17⁺TNF-α⁺, and IL-9⁺ within CD4⁺ and CD8⁺ T cells and of IL-6⁺CD4⁺ T cells were decreased in MNC-MSC co-cultures. MSCs decreased IL-10 and increased IL-4 mRNA expression in stimulated CD4⁺ and CD8⁺ T cells, whereas TGF-β was reduced in CD8⁺ and augmented in CD4⁺ T cells, with no changes for CTLA4. Finally, PMA + ionomycin stimulation did not induce significant alterations on MSCs phenotype but did increase indoleamine-2,3-dioxygenase (IDO), inducible costimulatory ligand (ICOSL), IL-1β, IL-8, and TNF-α mRNA expression.

Overall, our study showed that MSCs differentially regulate the functional compartments of CD4⁺ and CD8⁺ T cells, which may differentially impact their therapeutic effect in immune disorders. Furthermore, the influence of MSCs on IL-9 expression can open new possibilities for MSC-based therapy in allergic diseases.

The online version of this article (doi:10.1186/scrt537) contains supplementary material, which is available to authorized users.

• Autoimmunity
• Cancer
• Mesenchymal stem cells
• Sex hormones
• Systemic lupus erythematosus
• Th17

Current therapies for multiple sclerosis (MS) are largely palliative, not curative. Mesenchymal stem cells (MSCs) harbor regenerative and immunosuppressive functions, indicating a potential therapy for MS, yet the variability and low potency of MSCs from adult sources hinder their therapeutic potential. MSCs derived from human embryonic stem cells (hES-MSCs) may be better suited for clinical treatment of MS because of their unlimited and stable supply. Here, we show that hES-MSCs significantly reduce clinical symptoms and prevent neuronal demyelination in a mouse experimental autoimmune encephalitis (EAE) model of MS, and that the EAE disease-modifying effect of hES-MSCs is significantly greater than that of human bone-marrow-derived MSCs (BM-MSCs). Our evidence also suggests that increased IL-6 expression by BM-MSCs contributes to the reduced anti-EAE therapeutic activity of these cells. A distinct ability to extravasate and migrate into inflamed CNS tissues may also be associated with the robust therapeutic effects of hES-MSCs on EAE.

•

hES-MSCs show increased anti-EAE effects relative to adult human BM-MSCs

• cell therapy
• menstrual blood
• menstrual stem cells
• mesenchymal stem cells
• stem cells

• acute kidney injury
• ischaemia/reperfusion
• ischaemic conditioning
• kidney transplantation
• mesenchymal stromal cells