Transplanted allogeneic cardiac progenitor cells secrete GDF-15 and stimulate an active immune remodeling process in the ischemic myocardium.

BACKGROUND: Despite promising results in clinical studies, the mechanism for the beneficial effects of allogenic cell-based therapies remains unclear. Macrophages are not only critical mediators of inflammation but also critical players in cardiac remodeling. We hypothesized that transplanted allogenic rat cardiac progenitor cells (rCPCs) augment T-regulatory cells which ultimately promote proliferation of M2 like macrophages by an as-yet undefined mechanism. METHODS AND RESULTS: To test this hypothesis, we used crossover rat strains for exploring the mechanism of myocardial repair by allogenic CPCs. Human CPCs (hCPCs) were isolated from adult patients undergoing coronary artery bypass grafting, and rat CPCs (rCPCs) were isolated from male Wistar-Kyoto (WKY) rat hearts. Allogenic rCPCs suppressed the proliferation of T-cells observed in mixed lymphocyte reactions in vitro. Transplanted syngeneic or allogeneic rCPCs significantly increased cardiac function in a rat myocardial infarct (MI) model, whereas xenogeneic CPCs did not. Allogeneic rCPCs stimulated immunomodulatory responses by specifically increasing T-regulatory cells and M2 polarization, while maintaining their cardiac recovery potential and safety profile. Mechanistically, we confirmed the inactivation of NF-kB in Treg cells and increased M2 macrophages in the myocardium after MI by transplanted CPCs derived GDF15 and it's uptake by CD48 receptor on immune cells. CONCLUSION: Collectively, these findings strongly support the active immunomodulatory properties and robust therapeutic potential of allogenic CPCs in post-MI cardiac dysfunction.

[Arthrospira platensis phycocyanins: a perspective for use in foods for special dietary uses (brief review)].

Biomass of Arthrospira platensis has a long history of consumption as a source of protein, a number of micronutrients and minor biologically active compounds. Specific organoleptic properties of Arthrospira platensis biomass (pronounced bitter taste) limit its use as a source of phycocyanins. The developed modern methods of phycocyanin extraction from A. platensis biomass make it possible to obtain concentrates with improved sensory characteristics destined for the inclusion in foods for special dietary uses. The aim of this brief review was to analyze the results of the studies on the assessment of the biological activity of phycocyanin extracted from the Arthrospira platensis biomass, substantiating the prospects of using their concentrates for inclusion in foods for various dietary purposes. Material and methods. The PubMed Web Database, including MEDLINE article database, covering about 75% of the world's medical publications, was used for the main search for the literature. In addition, Scopus and Web of Science databases were used. Search depth - 15 years. Search keywords: Arthrospira platensis, phycocyanins, safety, antioxidant activity, immunomodulatory properties. Results and discussion. C-phycocyanin and allophycocyanin are complexes of proteins with the pigment phycocyanobilin, their total content is about 50% of the content of all proteins in the A. platensis biomass. A significant number of toxicological studies indicate that there are no risks to human health when using phycocyanin-containing extracts of A. platensis. Evidence of the antioxidant effect of phycocyanins extracted from A. platensis biomass, their anti-inflammatory activity, immunomodulatory properties, was obtained experimentally in vitro and in vivo, as well as in clinical studies. Conclusion. Toxicological studies and experimental in vivo tests have shown the safe and effective use of Arthrospira platensis biomass extracts with a high content of phycocyanins as an additional means of dietary prevention and diet therapy. These data indicate the prospects for conducting additional studies on the possibility of including phycocyanin concentrates in specialized foods for various purposes.

Lactobacillus rhamnosus postbiotic-induced immunomodulation as safer alternative to the use of live bacteria.

Many attempts have been made to search for safer immunomodulatory agents that enhance the immune response and reduce the number and severity of infections in at-risk populations. The use of postbiotics, non-viable microbial cells or cell fractions that confer a health benefit to the consumer, represents a safe and attractive way to modulate and enhance the immune function in order to improve human health. Therefore, the aim of this work is to evaluate the immunoregulatory effect of Lactobacillus rhamnosus CRL1505 postbiotics in a complex culture system using human intestinal epithelial cells (IECs) and dendritic cells (DCs) differentiated from peripheral blood mononuclear cells. First, we demonstrated that L. rhamnosus CRL1505 differentially modulate human IECs and DCs after the challenge with the TLR4 agonist LPS. The CRL1505 strain down-regulated CD40, CD80 and CD86 expression in DCs, and increased their production of TNF-α, IL-1ß, IL-6 and IL-10. Interestingly, the non-viable strain was able to modulate the immune response of both types of human cells. Then, we showed that cell wall (CW1505) and peptidoglycan (PG1505) from L. rhamnosus CRL1505 modulated TLR4-triggered immune response in IECs and DCs. Of interest, CW1505 showed a strong stimulatory effect while the PG1505 presented immune characteristics that were more similar to viable and non-viable CRL1505. To date, several molecules of immunobiotics were identified, that can be connected to specific host-responses. We hereby demonstrated that peptidoglycan of L. rhamnosus CRL1505 is a key molecule for the immunobiotic properties of this strain in human IECs and DCs. Likewise, the result of these studies could provide predictive tools for the in vivo efficacy of postbiotics and the scientific basis for their future applications in immunocompromised patients.

Chloroquine and hydroxychloroquine in antitumor therapies based on autophagy-related mechanisms.

Chloroquine (CQ) and hydroxychloroquine (HCQ) are the most common drugs used to relieve acute and chronic inflammatory diseases. In this article, we present a review about the use of CQ and HCQ in antitumor therapies based on autophagy mechanisms. These molecules break/discontinue autophagosome-lysosome fusions in initial phases and enhance antiproliferative action of chemotherapeutics. Their sensitizing effects of chemotherapy when used as an adjuvant option in clinical trials against cancer. However, human related-MDR genes are also under risk to develop chemo or radioresistance because cancer cells have ability to throw 4-aminoquinolines out from digestive vacuoles well. Additionally, they also have antitumor mechanism unrelated to autophagy, including cell death from apoptosis and necroptosis and immunomodulatory/anti-inflammatory properties. However, the link between some anticancer mechanisms, clinical efficacy and pharmacological safety has not yet been fully defined.

Insights into the Secretome of Mesenchymal Stem Cells and Its Potential Applications.

Mesenchymal stem cells (MSCs) have regenerative, immunoregulatory properties and can be easily isolated and expanded in vitro. Despite being a powerful tool for clinical applications, they present limitations in terms of delivery, safety, and variability of therapeutic response. Interestingly, the MSC secretome composed by cytokines, chemokines, growth factors, proteins, and extracellular vesicles, could represent a valid alternative to their use. It is noteworthy that MSC-derived extracellular vesicles (MSC-EVs) have the same effect and could be advantageous compared to the parental cells because of their specific miRNAs load. MiRNAs could be useful both in diagnostic procedures such as "liquid biopsy" to identify early pathologies and in the therapeutic field. Not only are MSC-EVs' preservation, transfer, and production easier, but their administration is also safer, hence some clinical trials are ongoing. However, much effort is required to improve the characterization of EVs to avoid artifacts and guarantee reproducibility of the studies.

Adipose mesenchymal stromal cells: Definition, immunomodulatory properties, mechanical isolation and interest for plastic surgery.

Ever since their discovery in 2001, adipose mesenchymal stromal cells (ASC) have profoundly modified clinical indications and our practice of plastic surgery, thereby placing our discipline at the forefront of regenerative medicine. These cells act through paracrine signaling by synthesizing immunosuppressive and pro-angiogenic factors. They are of key importance with regard to the regenerative properties of autologously grafted adipose tissue (AT). Taken together, they make up the stromal vascular fraction (SVF) comprising all AT cells except for adipocytes. As our knowledge evolves, we are moving from fat grafting towards SVF grafting, of which the essential sought-after effect is tissue regeneration. The objective of the present review is to synthesize present-day information on ASCs and their immunomodulatory properties and, from a practical standpoint, to indicate present-day and future steps towards establishment of clinical routine, particularly through application of techniques favoring mechanical digestion of adipose tissue.

Phenotypic and functional characterization of mesenchymal stromal cells isolated from pediatric patients with severe idiopathic nephrotic syndrome.

BACKGROUND: Idiopathic nephrotic syndrome (INS) is one of the most common renal diseases in the pediatric population; considering the role of the immune system in its pathogenesis, corticosteroids are used as first-line immunosuppressive treatment. Due to its chronic nature and tendency to relapse, a significant proportion of children experience co-morbidity due to prolonged exposure to corticosteroids and concomitant immunosuppression with second-line, steroid-sparing agents. Mesenchymal stromal cells (MSCs) are multipotent cells that represent a key component of the bone marrow (BM) microenvironment; given their unique immunoregulatory properties, their clinical use may be exploited as an alternative therapeutic approach in INS treatment. METHODS: In view of the possibility of exploiting their immunoregulatory properties, we performed a phenotypical and functional characterization of MSCs isolated from BM of five INS patients (INS-MSCs; median age, 13 years; range, 11-16 years) in comparison with MSCs isolated from eight healthy donors (HD-MSCs). MSCs were expanded ex vivo and then analyzed for their properties. RESULTS: Morphology, proliferative capacity, immunophenotype and differentiation potential did not differ between INS-MSCs and HD-MSCs. In an allogeneic setting, INS-MSCs were able to prevent both T- and B-cell proliferation and plasma-cell differentiation. In an in-vitro model of experimental damage to podocytes, co-culture with INS-MSCs appeared to be protective. DISCUSSION: Our results demonstrate that INS-MSCs maintain the main biological and functional properties typical of HD-MSCs; these data suggest that MSCs may be used in autologous cellular therapy approaches for INS treatment.

Therapeutic Potential of Autologous Adipose-Derived Stem Cells for the Treatment of Liver Disease.

Currently, the most effective therapy for liver diseases is liver transplantation, but its use is limited by organ donor shortage, economic reasons, and the requirement for lifelong immunosuppression. Mesenchymal stem cell (MSC) transplantation represents a promising alternative for treating liver pathologies in both human and veterinary medicine. Interestingly, these pathologies appear with a common clinical and pathological profile in the human and canine species; as a consequence, dogs may be a spontaneous model for clinical investigations in humans. The aim of this work was to characterize canine adipose-derived MSCs (cADSCs) and compare them to their human counterpart (hADSCs) in order to support the application of the canine model in cell-based therapy of liver diseases. Both cADSCs and hADSCs were successfully isolated from adipose tissue samples. The two cell populations shared a common fibroblast-like morphology, expression of stemness surface markers, and proliferation rate. When examining multilineage differentiation abilities, cADSCs showed lower adipogenic potential and higher osteogenic differentiation than human cells. Both cell populations retained high viability when kept in PBS at controlled temperature and up to 72 h, indicating the possibility of short-term storage and transportation. In addition, we evaluated the efficacy of autologous ADSCs transplantation in dogs with liver diseases. All animals exhibited significantly improved liver function, as evidenced by lower liver biomarkers levels measured after cells transplantation and evaluation of cytological specimens. These beneficial effects seem to be related to the immunomodulatory properties of stem cells. We therefore believe that such an approach could be a starting point for translating the results to the human clinical practice in future.

The effect of transplanted human Wharton's jelly mesenchymal stem cells treated with IFN-γ on experimental autoimmune encephalomyelitis mice.

Interferon gamma (IFN-γ) increases the immunosuppressive property of human Wharton's jelly mesenchymal stem cells (hWJ-MSCs). In this study, we evaluated the therapeutic effects of IFN-γ primed WJ-MSCs in EAE mice. IFN-γ primed WJ-MSCs were injected on days 3 and 11 after EAE induction. 21 days after EAE induction, splenocytes and cervical lymph node cells were isolated and cell proliferation, secretion of inflammatory cytokines and frequency of regulatory T-cells was measured. On day 50 of the study, cell infiltration and gene expression of inflammatory cytokines in brain of mice were studied. Leukocyte infiltration and symptoms were significantly reduced in IFN-γ primed WJ-MSCs treated group compared to other groups. These cells showed significantly reduced proliferation and increased Treg cells as well as decreased secretion and gene expression of inflammatory cytokines in EAE mice. Our data suggest that IFN-γ may be used to stimulate the immunomodulatory property of WJ-MSCs in clinical situations.

Human Adipose Stromal/Stem Cells from Obese Donors Show Reduced Efficacy in Halting Disease Progression in the Experimental Autoimmune Encephalomyelitis Model of Multiple Sclerosis.

Multiple sclerosis is an autoimmune disease that affects the white matter of the central nervous system and involves inflammation and demyelination. The recent advances in our understanding of adipose-derived stromal/stem cells (ASCs) and the utilization of these cells in clinical settings to treat diseases have made it essential to identify the most effective ASCs for therapy. Studies have not yet investigated the impact of obesity on the therapeutic efficacy of ASCs. Obesity is characterized by adipocyte hyperplasia and hypertrophy and can extend to metabolic and endocrine dysfunction. Investigating the impact obesity has on ASC biology will determine whether these cells are suitable for use in regenerative medicine. The therapeutic efficacy of ASCs isolated from lean subjects (body mass index [BMI] < 25; lnASCs) and obese subjects (BMI > 30; obASCs) were determined in murine experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis. Compared with the EAE disease-modifying effects of lnASCs, obASCs consistently failed to alleviate clinical symptoms or inhibit inflammation in the central nervous system. When activated, obASCs expressed higher mRNA levels of several pro-inflammatory cytokines compared with lnASCs. Additionally, conditioned media (CM) collected from the obASCs markedly enhanced the proliferation and differentiation of T cells; whereas, CM from lnASC did not. These results indicate that obesity reduces, or eliminates, the anti-inflammatory effects of human ASCs such that they may not be a suitable cell source for the treatment of autoimmune diseases. The data suggest that donor demographics may be particularly important when identifying suitable stem cells for treatment.

Immunomodulatory properties of Concholepas concholepas hemocyanin against francisellosis in a zebrafish model.

The development of vaccines for aquaculture has been an important milestone in providing a continuous and sustainable production. Most of the vaccines currently on the market for aquaculture include oil as adjuvant. Nevertheless, several studies reported an occurrence of side effects after their use in farmed fish. As a result, there is a need for new and improved adjuvants that can stimulate the immune system while causing as few side-effects as possible. Hemocyanins are versatile macromolecules with strong immunogenic and immunomodulatory properties. Due to these characteristics, hemocyanin from Concholepas concholepas (CCH) has been biochemically characterized and evaluated as vaccine adjuvant in mice and humans. Francisellosis is a chronic granulomatous disease, which can result in high mortality depending on the host. The disease is caused by the facultative intracellular Gram-negative bacteria Francisella noatunensis, which remains an unsolved problem for the aquaculture, as no efficient vaccines are available. The aim of the present work was to investigate the immunoregulatory properties of CCH against francisellosis in an experimental zebrafish model. When immunized with CCH, zebrafish were protected from subsequent challenge with a lethal dose of Francisella noatunensis subsp. orientalis. Subsequently the mRNA expression levels of several immune-related genes were studied, including mhcii, il12a, tnfα and ifng1-1. Taken together, the data report the immunoregulatory properties of CCH and its potential use as a vaccine adjuvant for aquaculture.

Overview of β-Glucans from Laminaria spp.: Immunomodulation Properties and Applications on Biologic Models.

Glucans are a group of glucose polymers that are found in bacteria, algae, fungi, and plants. While their properties are well known, their biochemical and solubility characteristics vary considerably, and glucans obtained from different sources can have different applications. Research has described the bioactivity of β-glucans extracted from the algae of the Laminaria genus, including in vivo and in vitro studies assessing pro- and anti-inflammatory cytokines, vaccine production, inhibition of cell proliferation, and anti- and pro-oxidant activity. Thus, the objective of this article was to review the potential application of β-glucans from Laminaria spp. in terms of their immunomodulatory properties, microorganism host interaction, anti-cancer activity and vaccine development.

Comprehensive characterization of mesenchymal stromal cells from patients with Fanconi anaemia.

Fanconi anaemia (FA) is an inherited disorder characterized by pancytopenia, congenital malformations and a predisposition to develop malignancies. Alterations in the haematopoietic microenvironment of FA patients have been reported, but little is known regarding the components of their bone marrow (BM) stroma. We characterized mesenchymal stromal cells (MSCs) isolated from BM of 18 FA patients both before and after allogeneic haematopoietic stem cell transplantation (HSCT). Morphology, fibroblast colony-forming unit (CFU-F) ability, proliferative capacity, immunophenotype, differentiation potential, ability to support long-term haematopoiesis and immunomodulatory properties of FA-MSCs were analysed and compared with those of MSCs expanded from 15 age-matched healthy donors (HD-MSCs). FA-MSCs were genetically characterized through conventional karyotyping, diepoxybutane-test and array-comparative genomic hybridization. FA-MSCs generated before and after HSCT were compared. Morphology, immunophenotype, differentiation potential, ability in vitro to inhibit mitogen-induced T-cell proliferation and to support long-term haematopoiesis did not differ between FA-MSCs and HD-MSCs. CFU-F ability and proliferative capacity of FA-MSCs isolated after HSCT were significantly lower than those of HD-MSCs. FA-MSCs reached senescence significantly earlier than HD-MSCs and showed spontaneous chromosome fragility. Our findings indicate that FA-MSCs are defective in their ability to survive in vitro and display spontaneous chromosome breakages; whether these defects are involved in pathophysiology of BM failure syndromes deserves further investigation.

Investigation of immunomodulatory properties of human Wharton's Jelly-derived mesenchymal stem cells after lentiviral transduction.

Human Wharton's Jelly-derived Mesenchymal Stem Cells (hWJ-MSCs) are considered as an alternative for bone-marrow-derived MSCs. These cells have immunosuppressive properties. It was unclear whether the WJ-MSCs would sustain their immunomodulatory characteristics after lentiviral transduction or not. In this study, we evaluated immunomodulatory properties of WJ-MSCs after lentiviral transduction. HWJ-MSCs were transduced with lentiviral particles. Expression of transduced and un-transduced hWJ-MSCs surface molecules and secretion of IL-10, HGF, VEGF and TGF-ß was analyzed. Cell proliferation and frequency of CD4(+)CD25(+) CD127(low/neg) Foxp3(+) T regulatory cells was measured. There was no difference between the surface markers and secretion of IL-10, HGF, VEGF and TGF-ß in transduced and un-transduced hWJ-MSCs. Both cells inhibited the proliferation of PHA stimulated PBMCs, and improved the frequency of T regulatory cells. These findings suggest that lentiviral transduction does not alter the immunomodulatory function of hWJ-MSCs. However, lentiviral transduction may have a wide range of applications in gene therapy.

Decoupling immunomodulatory properties from lipid binding in the α-pore-forming toxin Sticholysin II.

Sticholysin II (StII), a pore-forming toxin from the marine anemone Stichodactyla helianthus, enhances an antigen-specific cytotoxic T lymphocyte (CTL) response when co-encapsulated in liposomes with a model antigen. This capacity does not depend exclusively on its pore-forming activity and is partially supported by its ability to activate Toll-like receptor 4 (TLR4) in dendritic cells, presumably by interacting with this receptor or by triggering signaling cascades upon binding to lipid membrane. In order to investigate whether the lipid binding capacity of StII is required for immunomodulation, we designed a mutant in which the aromatic amino acids from the interfacial binding site Trp110, Tyr111 and Trp114 were substituted by Ala. In the present work, we demonstrated that StII3A keeps the secondary structure composition and global folding of StII, while it loses its lipid binding and permeabilization abilities. Despite this, StII3A upregulates dendritic cells maturation markers, enhances an antigen-specific effector CD8+ T cells response and confers antitumor protection in a preventive scenario in C57BL/6 mice. Our results indicate that a mechanism independent of its lipid binding ability is involved in the immunomodulatory capacity of StII, pointing to StII3A as a promising candidate to improve the reliability of the Sts-based vaccine platform.

Exploring the significance of microbiota metabolites in rheumatoid arthritis: uncovering their contribution from disease development to biomarker potential.

Rheumatoid arthritis (RA) is a multifaceted autoimmune disorder characterized by chronic inflammation and joint destruction. Recent research has elucidated the intricate interplay between gut microbiota and RA pathogenesis, underscoring the role of microbiota-derived metabolites as pivotal contributors to disease development and progression. The human gut microbiota, comprising a vast array of microorganisms and their metabolic byproducts, plays a crucial role in maintaining immune homeostasis. Dysbiosis of this microbial community has been linked to numerous autoimmune disorders, including RA. Microbiota-derived metabolites, such as short-chain fatty acids (SCFAs), tryptophan derivatives, Trimethylamine-N-oxide (TMAO), bile acids, peptidoglycan, and lipopolysaccharide (LPS), exhibit immunomodulatory properties that can either exacerbate or ameliorate inflammation in RA. Mechanistically, these metabolites influence immune cell differentiation, cytokine production, and gut barrier integrity, collectively shaping the autoimmune milieu. This review highlights recent advances in understanding the intricate crosstalk between microbiota metabolites and RA pathogenesis and also discusses the potential of specific metabolites to trigger or suppress autoimmunity, shedding light on their molecular interactions with immune cells and signaling pathways. Additionally, this review explores the translational aspects of microbiota metabolites as diagnostic and prognostic tools in RA. Furthermore, the challenges and prospects of translating these findings into clinical practice are critically examined.

Bioactive constituents from Tinospora cordifolia (willd.): Isolation, synthesis and their immunomodulatory activity.

Traditional medicinal plants have been used for centuries for their immunomodulatory properties and therapeutic potentials. The present study aims to investigate the immunomodulatory constituents from traditional medicinal plant, Tinospora cordifolia (willd.). Our study resulted in the isolation of new compound, 27-hydroxy octacosyl ferulate (1) along with eleven known compounds (2-12). The structures of the isolated compounds were characterized by combination of NMR (1D and 2D) and Mass spectroscopic methods. The hemisynthesis of compound 12 (ferulic acid) yielded (12a-12d and 12e-12 m) derivatives. Further, the isolated compounds and synthesized derivatives were assessed for their immunomodulatory potentials by evaluating their cytotoxicity and pro-inflammatory effects against macrophage cells (IL-6) and DC activation markers (CD 11c and 86). The biological results indicated that crude extract displayed potent immunomodulatory activity while isolated compounds and synthetic analogues showed moderate activity. Among the tested compounds, new compound (1), quercetin (10) and derivatives 12b, 12c found to be non-cytotoxic and displayed immunomodulatory potentials. Therefore, these compounds can be studied for autoimmunity and other immune suppressing conditions.

The Role of Mesenchymal Stem Cells in Modulating Adaptive Immune Responses in Multiple Sclerosis.

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system, leading to significant disability through neurodegeneration. Despite advances in the understanding of MS pathophysiology, effective treatments remain limited. Mesenchymal stem cells (MSCs) have gained attention as a potential therapeutic option due to their immunomodulatory and regenerative properties. This review examines MS pathogenesis, emphasizing the role of immune cells, particularly T cells, in disease progression, and explores MSCs' therapeutic potential. Although preclinical studies in animal models show MSC efficacy, challenges such as donor variability, culture conditions, migratory capacity, and immunological compatibility hinder widespread clinical adoption. Strategies like genetic modification, optimized delivery methods, and advanced manufacturing are critical to overcoming these obstacles. Further research is needed to validate MSCs' clinical application in MS therapy.

Immunomodulatory properties of mesenchymal stromal/stem cells: The link with metabolism.

BACKGROUND: Mesenchymal stromal/stem cells (MSCs) are the most promising stem cells for the treatment of multiple inflammatory and immune diseases due to their easy acquisition and potent immuno-regulatory capacities. These immune functions mainly depend on the MSC secretion of soluble factors. Recent studies have shown that the metabolism of MSCs plays critical roles in immunomodulation, which not only provides energy and building blocks for macromolecule synthesis but is also involved in the signaling pathway regulation. AIM OF REVIEW: A thorough understanding of metabolic regulation in MSC immunomodulatory properties can provide new sights to the enhancement of MSC-based therapy. KEY SCIENTIFIC CONCEPTS OF REVIEW: MSC immune regulation can be affected by cellular metabolism (glucose, adenosine triphosphate, lipid and amino acid metabolism), which further mediates MSC therapy efficiency in inflammatory and immune diseases. The enhancement of glycolysis of MSCs, such as signaling molecule activation, inflammatory cytokines priming, or environmental control can promote MSC immune functions and therapeutic potential. Besides glucose metabolism, inflammatory stimuli also alter the lipid molecular profile of MSCs, but the direct link with immunomodulatory properties remains to be further explored. Arginine metabolism, glutamine-glutamate metabolism and tryptophan-kynurenine via indoleamine 2,3-dioxygenase (IDO) metabolism all contribute to the immune regulation of MSCs. In addition to the metabolism dictating the MSC immune functions, MSCs also influence the metabolism of immune cells and thus determine their behaviors. However, more direct evidence of the metabolism in MSC immune abilities as well as the underlying mechanism requires to be uncovered.

The Role of COX-2 and PGE2 in the Regulation of Immunomodulation and Other Functions of Mesenchymal Stromal Cells.

The ability of MSCs to modulate the inflammatory environment is well recognized, but understanding the molecular mechanisms responsible for these properties is still far from complete. Prostaglandin E2 (PGE2), a product of the cyclooxygenase 2 (COX-2) pathway, is indicated as one of the key mediators in the immunomodulatory effect of MSCs. Due to the pleiotropic effect of this molecule, determining its role in particular intercellular interactions and aspects of cell functioning is very difficult. In this article, the authors attempt to summarize the previous observations regarding the role of PGE2 and COX-2 in the immunomodulatory properties and other vital functions of MSCs. So far, the most consistent results relate to the inhibitory effect of MSC-derived PGE2 on the early maturation of dendritic cells, suppressive effect on the proliferation of activated lymphocytes, and stimulatory effect on the differentiation of macrophages into M2 phenotype. Additionally, COX-2/PGE2 plays an important role in maintaining the basic life functions of MSCs, such as the ability to proliferate, migrate and differentiate, and it also positively affects the formation of niches that are conducive to both hematopoiesis and carcinogenesis.