Immunomodulatory properties of human adult and fetal multipotent mesenchymal stem cells

In recent years, a large number of studies have contributed to our understanding of the immunomodulatory mechanisms used by multipotent mesenchymal stem cells (MSCs). Initially isolated from the bone marrow (BM), MSCs have been found in many tissues but the strong immunomodulatory properties are best studied in BM MSCs. The immunomodulatory effects of BM MSCs are wide, extending to T lymphocytes and dendritic cells, and are therapeutically useful for treatment of immune-related diseases including graft-versus-host disease as well as possibly autoimmune diseases. However, BM MSCs are very rare cells and require an invasive procedure for procurement. Recently, MSCs have also been found in fetal-stage embryo-proper and extra-embryonic tissues, and these human fetal MSCs (F-MSCs) have a higher proliferative profile, and are capable of multilineage differentiation as well as exert strong immunomodulatory effects. As such, these F-MSCs can be viewed as alternative sources of MSCs. We review here the current understanding of the mechanisms behind the immunomodulatory properties of BM MSCs and F-MSCs. An increase in our understanding of MSC suppressor mechanisms will offer insights for prevalent clinical use of these versatile adult stem cells in the near future.     

Immunosuppressive properties of mesenchymal stem cells: advances and applications

Mesenchymal stem cells (MSCs) have been isolated from a variety of tissues, such as bone marrow, skeletal muscle, dental pulp, bone, umbilical cord and adipose tissue. MSCs are used in regenerative medicine mainly based on their capacity to differentiate into specific cell types and also as bioreactors of soluble factors that will promote tissue regeneration from the damaged tissue cellular progenitors. In addition to these regenerative properties, MSCs hold an immunoregulatory capacity, and elicit immunosuppressive effects in a number of situations. Not only are they immunoprivileged cells, due to the low expression of class II Major Histocompatibilty Complex (MHC-II) and costimulatory molecules in their cell surface, but they also interfere with different pathways of the immune response by means of direct cell-to-cell interactions and soluble factor secretion. In vitro, MSCs inhibit cell proliferation of T cells, B-cells, natural killer cells (NK) and dendritic cells (DC), producing what is known as division arrest anergy. Moreover, MSCs can stop a variety of immune cell functions: cytokine secretion and cytotoxicity of T and NK cells; B cell maturation and antibody secretion; DC maturation and activation; as well as antigen presentation. It is thought that MSCs need to be activated to exert their immunomodulation skills. In this scenario, an inflammatory environment seems to be necessary to promote their effect and some inflammation-related molecules such as tumor necrosis factor-α and interferon-γ might be implicated. It has been observed that MSCs recruit T-regulatory lymphocytes (Tregs) to both lymphoid organs and graft. There is great controversy concerning the mechanisms and molecules involved in the immunosuppressive effect of MSCs. Prostaglandin E2, transforming growth factor-β, interleukins- 6 and 10, human leukocyte antigen-G5, matrix metalloproteinases, indoleamine-2,3-dioxygenase and nitric oxide are all candidates under investigation. In vivo studies have shown many discrepancies regarding the immunomodulatory properties of MSCs. These studies have been designed to test the efficacy of MSC therapy in two different immune settings: the prevention or treatment of allograft rejection episodes, and the ability to suppress abnormal immune response in autoimmune and inflammatory diseases. Preclinical studies have been conducted in rodents, rabbits and baboon monkeys among others for bone marrow, skin, heart, and corneal transplantation, graft versus host disease, hepatic and renal failure, lung injury, multiple sclerosis, rheumatoid arthritis, diabetes and lupus diseases. Preliminary results from some of these studies have led to human clinical trials that are currently being carried out. These include treatment of autoimmune diseases such as Crohn's disease, ulcerative colitis, multiple sclerosis and type 1 diabetes mellitus; prevention of allograft rejection and enhancement of the survival of bone marrow and kidney grafts; and treatment of resistant graft versus host disease. We will try to shed light on all these studies, and analyze why the results are so contradictory.     

Disparate Effects of Mesenchymal Stem Cells in Experimental Autoimmune Encephalomyelitis and Cuprizone-Induced Demyelination

Mesenchymal stem cells (MSCs) are pleiotropic cells with potential therapeutic benefits for a wide range of diseases. Because of their immunomodulatory properties they have been utilized to treat autoimmune diseases such as multiple sclerosis (MS), which is characterized by demyelination. The microenvironment surrounding MSCs is thought to affect their differentiation and phenotype, which could in turn affect the efficacy. We thus sought to dissect the potential for differential impact of MSCs on central nervous system (CNS) disease in T cell mediated and non-T cell mediated settings using the MOG_35–55 experimental autoimmune encephalomyelitis (EAE) and cuprizone-mediated demyelination models, respectively. As the pathogeneses of MS and EAE are thought to be mediated by IFNγ-producing (T_H1) and IL-17A-producing (T_H17) effector CD4+ T cells, we investigated the effect of MSCs on the development of these two key pathogenic cell groups. Although MSCs suppressed the activation and effector function of T_H17 cells, they did not affect T_H1 activation, but enhanced T_H1 effector function and ultimately produced no effect on EAE. In the non- T cell mediated cuprizone model of demyelination, MSC administration had a positive effect, with an overall increase in myelin abundance in the brain of MSC-treated mice compared to controls. These results highlight the potential variability of MSCs as a biologic therapeutic tool in the treatment of autoimmune disease and the need for further investigation into the multifaceted functions of MSCs in diverse microenvironments and the mechanisms behind the diversity.     

Immunomodulation by mesenchymal stem cells:Interplay between mesenchymal stem cells and regulatory lymphocytes

Mesenchymal stem cells(MSCs) possess immunomodulatory properties, which confer enormous potential for clinical application. Considerable evidence revealed their efficacy on various animal models of autoimmune diseases, such as multiple sclerosis, systemic lupus erythematosus and uveitis. MSCs elicit their immunomodulatory effects by inhibiting lymphocyte activation and proliferation, forbidding the secretion of proinflammatory cytokines, limiting the function of antigen presenting cells, and inducing regulatory T(Treg) and B(Breg) cells. The induction of Treg and Breg cells is of particular interest since Treg and Breg cells have significant roles in maintaining immune tolerance. Several mechanisms have been proposed regarding to the MSCs-mediated induction of Treg and Breg cells. Accordingly, MSCs induce regulatory lymphocytes through secretion of multiple pleiotropic cytokines, cell-to-cell contact with target cells and modulation of antigen-presenting cells. Here, we summarized how MSCs induce Treg and Breg cells to provoke immunosuppression.     

Mesenchymal stem cells and immunomodulation: current status and future prospects

The unique immunomodulatory properties of mesenchymal stem cells (MSCs) make them an invaluable cell type for the repair of tissue/ organ damage caused by chronic inflammation or autoimmune disorders. Although they hold great promise in the treatment of immune disorders such as graft versus host disease (GvHD) and allergic disorders, there remain many challenges to overcome before their widespread clinical application. An understanding of the biological properties of MSCs will clarify the mechanisms of MSC-based transplantation for immunomodulation. In this review, we summarize the preclinical and clinical studies of MSCs from different adult tissues, discuss the current hurdles to their use and propose the future development of pluripotent stem cell-derived MSCs as an approach to immunomodulation therapy.     

The effect of pro-inflammatory cytokines on immunophenotype,differentiation capacity and immunomodulatory functions of human mesenchymal stem cells

Mesenchymal stem cells (MSCs), as cells with potential clinical utilities, have demonstrated preferential incorporation into inflammation sites. Immunophenotype and immunomodulatory functions of MSCs could alter by inflamed-microenvironments due to the local pro-inflammatory cytokine milieu. A major cellular mediator with specific function in promoting inflammation and pathogenicity of autoimmunity are IL-17-producing T helper 17 (Th17) cells that polarize in inflamed sites in the presence of pro-inflammatory cytokines such as Interleukin-1β (IL-1β), IL-6 and IL-23. Since MSCs are promising candidate for cell-based therapeutic strategies in inflammatory and autoimmune diseases, Th17 cell polarizing factors may alter MSCs phenotype and function. In this study, human bone-marrow-derived MSCs (BM-MSC) and adipose tissue-derived MSCs (AD-MSC) were cultured with or without IL-1β, IL-6 and IL-23 as pro-inflammatory cytokines. The surface markers and their differentiation capacity were measured in cytokine-untreated and cytokine-treated MSCs. MSCs-mediated immunomodulation was analyzed by their regulatory effects on mixed lymphocyte reaction (MLR) and the level of IL-10, TGF-β, IL-4, IFN-γ and TNF-α production as immunomodulatory cytokines. Pro-inflammatory cytokines showed no effect on MSCs morphology, immunophenotype and co-stimulatory molecules except up-regulation of CD45. Adipogenic and osteogenic differentiation capacity increased in CD45+ MSCs. Moreover, cytokine-treated MSCs preserved the suppressive ability of allogeneic T cell proliferation and produced higher level of TGF-β and lower level of IL-4. We concluded pro-inflammatory cytokines up-regulate the efficacy of MSCs in cell-based therapy of degenerative, inflammatory and autoimmune disorders.     

骨髓间充质干细胞的免疫学研究进展

间充质干细胞（mesenchymal stem cells,MSCs）是骨髓中除造血干细胞以外的另一种成体干细胞,广泛分布于动物体内骨髓、肝脏、脂肪等多种组织中。MSCS具有强大的自我更新能力和多向分化潜能,是移植领域应用前景广阔的再生来源细胞;同时,MSCs是一种重要的免疫调节细胞,MSCs在炎症细胞因子刺激后对免疫系统表现出很强的抑制作用,所以MSCs有望应用于减少免疫排斥,延长移植物存活时间,治疗相关免疫失调症,如自身免疫疾病等方面。本文主要对间充质干细胞与免疫系统相互作用的研究做相关介绍。     

Mesenchymal stem cell-based therapy for the treatment of type 1 diabetes mellitus

The pathophysiology of Type 1 diabetes (T1D) appears largely related to an innate defect in the immune system culminating in a loss of self tolerance and destruction of the insulin producing β-cells. Currently, there is no definitive cure for diabetes. Insulin injection does not mimic the precise regulation of β-cells on glucose homeostasis, leading long term to the development of complications. Other therapeutic approaches therefore, are necessary and cell therapy is thought to be a possible approach. In this sense, mesenchymal stem cells (MSCs) can offer a promising possibility that deserves to be explored. MSCs are multipotent non-hematopoietic progenitor cells. Their therapeutic potentials have recently been brought into the spotlights of many fields of research. Although the regenerative capabilities of MSCs have been a driving force to initiate studies testing their therapeutic effectiveness, their immunomodulatory properties have been equally exciting. MSCs possess specific immunomodulatory properties that would appear capable of disabling immune dysregulation that leads to β-cell destruction in T1D. Furthermore, MSCs can be sequentially cultured in specially defined conditions and their differentiation extends toward the β-cell phenotype and the formation of insulin producing cells (IPCs). To date, the role of MSCs in T1D remains completely unexplored. We herein summarize multiple strategies that have been proposed and tested for its potential therapeutic benefit for T1D.     

Mesenchymal stem cells in the treatment of inflammatory and autoimmune diseases in experimental animal models

Multipotent mesenchymal stromal cells [also known as mesenchymal stem cells(MSCs)] are currently being studied as a cell-based treatment for inflammatory disorders. Experimental animal models of human immune-mediated diseases have been instrumental in establishing their immunosuppressive properties. In this review, we summarize recent studies examining the effectiveness of MSCs as immunotherapy in several widely-studied animal models, including type 1 diabetes, experimental autoimmune arthritis, experimental autoimmune encephalomyelitis, inflammatory bowel disease, graft-vs-host disease, and systemic lupus erythematosus. In addition, we discuss mechanisms identified by which MSCs mediate immune suppression in specific disease models, and potential sources of functional variability of MSCs between studies.     

Early intervention with gene-modified mesenchymal stem cells overexpressing interleukin-4 enhances anti-inflammatory responses and functional recovery in experimental autoimmune demyelination

Mesenchymal stem/stromal cells (MSCs) can be isolated from most adult tissues and hold considerable promise for tissue regenerative therapies. Some of the potential advantages that MSCs have over other adult stem cell types include: (1) their relative ease of isolation, culture and expansion; (2) their immunomodulatory properties; (3) they can provide trophic support to injured tissues; (4) they can be transduced by retroviral vectors at a high efficiency; (5) they have an ability to home to sites of inflammation and injury. Collectively these characteristics suggest that MSCs are attractive vehicles for cell and gene therapy applications. In the current study, we investigated whether transplantation of human adipose-derived MSCs (Ad-MSCs) engineered to overexpress the anti-inflammatory cytokine interleukin (IL)-4 was efficacious in experimental autoimmune encephalomyelitis (EAE). Ad-MSCs transduced with a bicistronic lentiviral vector encoding mouse IL-4 and enhanced green fluorescent protein (Ad-IL4-MSCs) stably expressed, relatively high levels of both transgenes. Importantly the phenotypic and functional attributes of Ad-IL4-MSCs, such as the expression of homing molecules and differentiation capacity, was not altered by the transduction process. Notably, the early administration of Ad-IL4-MSCs in mice with EAE at the time of T-cell priming attenuated clinical disease. This protective effect was associated with a reduction in peripheral MOG-specific T-cell responses and a shift from a pro- to an anti-inflammatory cytokine response. These data suggest that the delivery of Ad-MSCs genetically engineered to express anti-inflammatory cytokines may provide a rational approach to promote immunomodulation and tissue protection in a number of inflammatory and degenerative diseases including multiple sclerosis.     

Early intervention with gene-modified mesenchymal stem cells overexpressing interleukin-4 enhances anti-inflammatory responses and functional recovery in experimental autoimmune demyelination

Mesenchymal stem/stromal cells (MSCs) can be isolated from most adult tissues and hold considerable promise for tissue regenerative therapies. Some of the potential advantages that MSCs have over other adult stem cell types include: (1) their relative ease of isolation, culture and expansion; (2) their immunomodulatory properties; (3) they can provide trophic support to injured tissues; (4) they can be transduced by retroviral vectors at a high efficiency; (5) they have an ability to home to sites of inflammation and injury. Collectively these characteristics suggest that MSCs are attractive vehicles for cell and gene therapy applications. In the current study, we investigated whether transplantation of human adipose-derived MSCs (Ad-MSCs) engineered to overexpress the anti-inflammatory cytokine interleukin (IL)-4 was efficacious in experimental autoimmune encephalomyelitis (EAE). Ad-MSCs transduced with a bicistronic lentiviral vector encoding mouse IL-4 and enhanced green fluorescent protein (Ad-IL4-MSCs) stably expressed, relatively high levels of both transgenes. Importantly the phenotypic and functional attributes of Ad-IL4-MSCs, such as the expression of homing molecules and differentiation capacity, was not altered by the transduction process. Notably, the early administration of Ad-IL4-MSCs in mice with EAE at the time of T-cell priming attenuated clinical disease. This protective effect was associated with a reduction in peripheral MOG-specific T-cell responses and a shift from a pro- to an anti-inflammatory cytokine response. These data suggest that the delivery of Ad-MSCs genetically engineered to express anti-inflammatory cytokines may provide a rational approach to promote immunomodulation and tissue protection in a number of inflammatory and degenerative diseases including multiple sclerosis.     

Immunomodulatory properties of dental tissue-derived mesenchymal stem cells: Implication in disease and tissue regeneration

Mesenchymal stem cells (MSCs) are considered as an attractive tool for tissue regeneration and possess a strong immunomodulatory ability. Dental tissue-derived MSCs can be isolated from different sources, such as the dental pulp, periodontal ligament, deciduous teeth, apical papilla, dental follicles and gingiva. According to numerous in vitro studies, the effect of dental MSCs on immune cells might depend on several factors, such as the experimental setting, MSC tissue source and type of immune cell preparation. Most studies have shown that the immunomodulatory activity of dental MSCs is strongly upregulated by activated immune cells. MSCs exert mostly immunosuppressive effects, leading to the dampening of immune cell activation. Thus, the reciprocal interaction between dental MSCs and immune cells represents an elegant mechanism that potentially contributes to tissue homeostasis and inflammatory disease progression. Although the immunomodulatory potential of dental MSCs has been extensively investigated in vitro, its role in vivo remains obscure. A few studies have reported that the MSCs isolated from inflamed dental tissues have a compromised immunomodulatory ability. Moreover, the expression of some immunomodulatory proteins is enhanced in periodontal disease and even shows some correlation with disease severity. MSC-based immunomodulation may play an essential role in the regeneration of different dental tissues. Therefore, immunomodulation-based strategies may be a very promising tool in regenerative dentistry.     

Ligation of TLR2 and TLR4 on murine bone marrow-derived mesenchymal stem cells triggers differential effects on their immunosuppressive activity

Mesenchymal stem cells (MSCs) have potent regulatory effects on immune and inflammatory responses. Recently the findings of functional TLR expression on MSC implicates these receptors in the function established for MSCs. Here we specially investigated the effects of TLR2, 4 ligation in mice MSC on migration, modulation of allogeneic mixed lymphocytes reaction (allo-MLR) and inducing Treg cells. We demonstrated that ligation of TLR2, but not TLR4, could significantly inhibit migration of MSC, impair MSC-mediated immunosuppression on allo-MLR, and reduce MSC-mediated expansion of CD4+CD25+Foxp3+ regulatory T cells. Compared with TLR4 activated MSCs and non-TLR activated MSC, TLR2 activation induced a relatively lower level of CXCL-10 mRNA and protein expressions which has been elucidated to act in concert with other soluble factor in MSC-mediated immunomodulation. These data indicate that TLR2 and TLR4 ligation had different effects on immunomodulatory capability of murine BMSCs, which should be considered in their use for treating inflammatory diseases.     

Mesenchymal stem cell therapy and acute graft-versus-host disease: a review

Mesenchymal stem cells (MSCs) are being widely studied as potential cell therapy agents due to their immunomodulatory properties, which have been established by in vitro studies and in several clinical trials. Within this context, mesenchymal stem cell therapy appears to hold substantial promise, particularly in the treatment of conditions involving autoimmune and inflammatory components. Nevertheless, many research findings are still contradictory, mostly due to difficulties in characterization of the effects of MSCs in vivo. The purpose of this review is to report the mechanisms underlying mesenchymal stem cell therapy for acute graft-versus-host disease, particularly with respect to immunomodulation, migration, and homing, as well as report clinical applications described in the literature.     

Umbilical cord–derived mesenchymal stromal cells in cardiovascular disease: review of preclinical and clinical data

The human umbilical cord has recently emerged as an attractive potential source of mesenchymal stromal cells (MSCs) to be adopted for use in regenerative medicine. Umbilical cord MSCs (UC-MSCs) not only share the same features of all MSCs such as multi-lineage differentiation, paracrine functions and immunomodulatory properties, they also have additional advantages, such as no need for bone marrow aspiration and higher self-renewal capacities. They can be isolated from various compartments of the umbilical cord (UC) and can be used for autologous or allogeneic purposes. In the past decade, they have been adopted in cardiovascular disease and have shown promising results mainly due to their pro-angiogenic and anti-inflammatory properties. This review offers an overview of the biological properties of UC-MSCs describing available pre-clinical and clinical data with respect to their potential therapeutic use in cardiovascular regeneration, with current challenges and future directions discussed.     

In vitro and in vivo neurogenic potential of mesenchymal stem cells isolated from different sources

Regenerative medicine is an evolving interdisciplinary topic of research involving numerous technological methods that utilize stem cells to repair damaged tissues. Particularly, mesenchymal stem cells (MSCs) are a great tool in regenerative medicine because of their lack of tumorogenicity, immunogenicity and ability to perform immunomodulatory as well as anti-inflammatory functions. Numerous studies have investigated the role of MSCs in tissue repair and modulation of allogeneic immune responses. MSCs derived from different sources hold unique regenerative potential as they are self-renewing and can differentiate into chondrocytes, osteoblasts, adipocytes, cardiomyocytes, hepatocytes, endothelial and neuronal cells, among which neuronal-like cells have gained special interest. MSCs also have the ability to secrete multiple bioactive molecules capable of stimulating recovery of injured cells and inhibiting inflammation. In this review we focus on neural differentiation potential of MSCs isolated from different sources and how certain growth factors/small molecules can be used to derive neuronal phenotypes from MSCs. We also discuss the efficacy of MSCs when transplanted in vivo and how they can generate certain neurons and lead to relief or recovery of the diseased condition. Furthermore, we have tried to evaluate the appropriate merits of different sources of MSCs with respect to their propensity towards neurological differentiation as well as their effectiveness in preclinical studies.     

Mesenchymal stem cells targeting the GVHD

Acute graft-versus-host disease(GVHD) occurs after allogeneic hematopoietic stem cell transplant and is a reaction of donor immune cells against host tissues.About 35%—50% of hematopoietic stem cell transplant(HSCT) recipients will develop acute GVHD.It is associated with considerable morbidity and mortality,particularly in patients who do not respond to primary therapy,which usually consists of glucocorticoids(steroids).Most of the available second-line and third-line treatments for steroid-refractory acut...     

Isolation and characterization of mesenchymal stem cells in orthopaedics and the emergence of compact bone mesenchymal stem cells as a promising surgical adjunct

The potential clinical and economic impact of mesenchymal stem cell (MSC) therapy is immense. MSCs act through multiple pathways: (1) as “trophic” cells, secreting various factors that are immunomodulatory, anti-inflammatory, anti-apoptotic, proangiogenic, proliferative, and chemoattractive; (2) in conjunction with cells native to the tissue they reside in to enhance differentiation of surrounding cells to facilitate tissue regrowth. Researchers have developed methods for the extraction and expansion of MSCs from animal and human tissues. While many sources of MSCs exist, including adipose tissue and iliac crest bone graft, compact bone (CB) MSCs have shown great potential for use in orthopaedic surgery. CB MSCs exert powerful immunomodulatory effects in addition to demonstrating excellent regenerative capacity for use in filling boney defects. CB MSCs have been shown to have enhanced response to hypoxic conditions when compared with other forms of MSCs. More work is needed to continue to characterize the potential applications for CB MSCs in orthopaedic trauma.     

Mesenchymal stem cells: Emerging mechanisms of immunomodulation and therapy

Mesenchymal stem cells (MSCs) are a pleiotropic population of cells that are self-renewing and capable of differentiating into canonical cells of the mesenchyme, including adipocytes, chondrocytes, and osteocytes. They employ multi-faceted approaches to maintain bone marrow niche homeostasis and promote wound healing during injury. Biomedical research has long sought to exploit their pleiotropic properties as a basis for cell therapy for a variety of diseases and to facilitate hematopoietic stem cell establishment and stromal reconstruction in bone marrow transplantation. Early results demonstrated their usage as safe, and there was little host response to these cells. The discovery of their immunosuppressive functions ushered in a new interest in MSCs as a promising therapeutic tool to suppress inflammation and down-regulate pathogenic immune responses in graft-versus-host and autoimmune diseases such as multiple sclerosis, autoimmune diabetes, and rheumatoid arthritis. MSCs produce a large number of soluble and membrane-bound factors, some of which inhibit immune responses. However, the full range of MSC-mediated immune-modulation remains incompletely understood, as emerging reports also reveal that MSCs can adopt an immunogenic phenotype, stimulate immune cells, and yield seemingly contradictory results in experimental animal models of inflammatory disease. The present review describes the large body of literature that has been accumulated on the fascinating biology of MSCs and their complex effects on immune responses.     

Mesenchymal stem cell therapy for the treatment of inflammatory diseases: Challenges,opportunities, and future perspectives

Mesenchymal stem cells (MSCs) are promising alternative agents for the treatment of inflammatory disorders due to their immunomodulatory functions, and several clinical trials on MSC-based products are currently being conducted. In this review, we discuss recent progress made on the use of MSCs as immunomodulatory agents, developmental challenges posed by MSC-based therapy, and the strategies being used to overcome these challenges. In this context, current understanding of the mechanisms responsible for MSC interactions with the immune system and the molecular responses of MSCs to inflammatory signals are discussed. The immunosuppressive activities of MSCs are initiated by cell-to-cell contact and the release of immuno-regulatory molecules. By doing so, MSCs can inhibit the proliferation and function of T cells, natural killer cells, B cells, and dendritic cells, and can also increase the proliferation of regulatory T cells. However, various problems, such as low transplanted cell viability, poor homing and engraftment into injured tissues, MSC heterogeneity, and lack of adequate information on optimum MSC doses impede clinical applications. On the other hand, it has been shown that the immunomodulatory activities and viabilities of MSCs might be enhanced by 3D-cultured systems, genetic modifications, preconditioning, and targeted-delivery.