Immune effects of mesenchymal stromal cells in experimental stroke.
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ABSTRACT:
SUBMITTER: Scheibe F
PROVIDER: S-EPMC3421097 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundMesenchymal stromal cells (MSCs) are believed to be hypoimmunogeneic with potential use for allogeneic administration.MethodsBone marrow was harvested from Connemara (n = 1), Standardbred (n = 6), and Thoroughbred (n = 3) horses. MSCs were grouped by their level of expression of major histocompatibility factor II (MHC II). MSCs were then sub-grouped by those MSCs derived from universal blood donor horses. MSCs were isolated and cultured using media containing fetal bovine serum until adequate numbers were acquired. The MSCs were cultured in xenogen-free media for 48 h prior to use and during all assays. Autologous and allogeneic MSCs were then directly co-cultured with responder leukocytes from the Connemara horse in varying concentrations of MSCs to leukocytes (1:1, 1:10, and 1:100). MSCs were also cultured with complement present and heat-inactivated complement to determine whether complement alone would decrease MSC viability. MSCs underwent haplotyping of their equine leukocyte antigen (ELA) to determine whether the MHC factors were matched or mismatched between the donor MSCs and the responder leukocytes.ResultsAll allogeneic MSCs were found to be ELA mismatched with the responder leukocytes. MHC II-low and universal blood donor MSCs caused no peripheral blood mononuclear cell (PBMC) proliferation, no increase in B cells, and no activation of CD8 lymphocytes. Universal blood donor MSCs stimulated a significant increase in the number of T regulatory cells. Neutrophil interaction with MSCs showed that universal blood donor and MHC II-high allogeneic MSCs at the 6 h time point in co-culture caused greater neutrophil activation than the other co-culture groups. Complement-mediated cytotoxicity did not consistently cause MSC death in cultures with active complement as compared to those with inactivated complement. Gene expression assays revealed that the universal blood donor group and the MHC II-low MSCs were more metabolically active both in the anabolic and catabolic gene categories when cultured with allogeneic lymphocytes as compared to the other co-cultures. These upregulated genes included CD59, FGF-2, HGF, IDO, IL-10, IL-RA, IL-2, SOX2, TGF-β1, ADAMSTS-4, ADAMSTS-5, CCL2, CXCLB/IL-8, IFNγ, IL-1β, and TNFα.ConclusionsMHC II-low MSCs are the most appropriate type of allogeneic MSC to prevent activation of the innate and cell-mediated component of the adaptive immune systems and have increased gene expression as compared to other allogeneic MSCs.
| S-EPMC8588742 | biostudies-literature
Project description:BACKGROUND:Silicosis is an occupational disease that affects workers who inhale silica particles, leading to extensive lung fibrosis and ultimately causing respiratory failure. Mesenchymal stromal cells (MSCs) have been shown to exert therapeutic effects in lung diseases and represent an alternative treatment for silicosis. Recently, it has been suggested that similar effects can be achieved by the therapeutic use of extracellular vesicles (EVs) obtained from MSCs. The aim of this study was to investigate the effects of adipose-tissue-derived MSCs (AD-MSCs) or their EVs in a model of silicosis. METHODS:Silicosis was induced by intratracheal instillation of silica in C57BL/6 mice. After the onset of disease, animals received saline, AD-MSCs, or EVs, intratracheally. RESULTS:At day 30, AD-MSCs and EVs led to a reduction in collagen fiber content, size of granuloma, and in the number of macrophages inside granuloma and in the alveolar septa. In addition, the expression levels of interleukin 1? and transforming growth factor beta in the lungs were decreased. Higher dose of EVs also reduced lung static elastance when compared with the untreated silicosis group. CONCLUSIONS:Both AD-MSCs and EVs, locally delivered, ameliorated fibrosis and inflammation, but dose-enhanced EVs yielded better therapeutic outcomes in this model of silicosis.
| S-EPMC5975461 | biostudies-literature
Project description:Asthma is a chronic inflammatory disease characterized by airway inflammation and remodeling, which can lead to progressive decline of lung function. Although mesenchymal stromal cells (MSCs) have shown beneficial immunomodulatory properties in preclinical models of allergic asthma, effects on airway remodeling have been limited. Mounting evidence suggests that prior exposure of MSCs to specific inflammatory stimuli or environments can enhance their immunomodulatory properties. Therefore, we investigated whether stimulating MSCs with bronchoalveolar lavage fluid (BALF) or serum from asthmatic mice could potentiate their therapeutic properties in experimental asthma. In a house dust mite (HDM) extract asthma model in mice, unstimulated, asthmatic BALF-stimulated, or asthmatic serum-stimulated MSCs were administered intratracheally 24 hours after the final HDM challenge. Lung mechanics and histology; BALF protein, cellularity, and biomarker levels; and lymph-node and bone marrow cellularity were assessed. Compared with unstimulated or BALF-stimulated MSCs, serum-stimulated MSCs further reduced BALF levels of interleukin (IL)-4, IL-13, and eotaxin, total and differential cellularity in BALF, bone marrow and lymph nodes, and collagen fiber content, while increasing BALF IL-10 levels and improving lung function. Serum stimulation led to higher MSC apoptosis, expression of various mediators (transforming growth factor-?, interferon-?, IL-10, tumor necrosis factor-?-stimulated gene 6 protein, indoleamine 2,3-dioxygenase-1, and IL-1 receptor antagonist), and polarization of macrophages to M2 phenotype. In conclusion, asthmatic serum may be a novel strategy to potentiate therapeutic effects of MSCs in experimental asthma, leading to further reductions in both inflammation and remodeling than can be achieved with unstimulated MSCs. Stem Cells Translational Medicine 2019;8:301&312.
| S-EPMC6392406 | biostudies-literature
Project description:Bone marrow-derived stromal cells or mesenchymal stromal cells (BMSCs or MSCs, as we will call them in this work) are multipotent progenitor cells that can differentiate into osteoblasts, adipocytes and chondrocytes. In addition, MSCs have been shown to modulate the function of a variety of immune cells. Donor age has been shown to affect the regenerative potential, differentiation, proliferation and anti-inflammatory potency of MSCs; however, the impact of donor age on their immunosuppressive activity is unknown. In this study, we evaluated the ability of MSCs derived from very young children and adults on T-cell suppression and cytokine secretion by monocytes/macrophages. MSCs were obtained from extra digits of children between 10 and 21 months and adults between 28 and 64 years of age. We studied cell surface marker expression, doubling time, lineage differentiation potential and immunosuppressive function of the MSCs. Young MSCs double more quickly and differentiate into bone and fat cells more efficiently than those from older donors. They also form more and dense colonies of fibroblasts (colony forming unit-fibroblast [CFU-F]). MSCs from both young and adult subjects suppressed T-cell proliferation in a mitogen-induced assay at 1:3 and 1:30 ratios. At a 1:30 ratio, however, MSCs from adults did not, but MSCs from infants did suppress T-cell proliferation. In the mixed lymphocyte reaction assay, MSCs from infants produced similar levels of suppression at all three MSC/T-cell ratios, but adult MSCs only inhibited T-cell proliferation at a 1:3 ratio. Cytokine analyses of co-cultures of MSCs and macrophages showed that both adult and young MSCs suppress tumor necrosis factor alpha (TNF-α) and induce interleukin-10 (IL-10) production in macrophage co-culture assay in a similar manner. Overall, this work shows that developing MSCs display a higher level of immunosuppression than mature MSCs.
| S-EPMC6435420 | biostudies-literature
Project description:Coronavirus disease 2019 (COVID-19) may result in a life-threatening condition due to a hyperactive immune reaction to severe acute respiratory syndrome-coronavirus-2 infection, for which no effective treatment is available. Based on the potent immunomodulatory properties of mesenchymal stromal cells (MSCs), a growing number of trials are ongoing. This prompted us to carry out a thorough immunological study in a patient treated with umbilical cord-derived MSCs and admitted to the Intensive Care Unit for COVID-19-related pneumonia. The exploratory analyses were assessed on both peripheral blood and bronchoalveolar fluid lavage samples at baseline and after cellular infusion by means of single-cell RNA sequencing, flow cytometry, ELISA, and functional assays. Remarkably, a normalization of circulating T lymphocytes count paralleled by a reduction of inflammatory myeloid cells, and a decrease in serum levels of pro-inflammatory cytokines, mostly of interleukin-6 and tumor necrosis factor-α, were observed. In addition, a drop of plasma levels of those chemokines essential for neutrophil recruitment became evident that paralleled the decrease of lung-infiltrating inflammatory neutrophils. Finally, circulating monocytes and low-density gradient neutrophils acquired immunosuppressive function. This scenario was accompanied by an amelioration of respiratory, renal, inflammatory, and pro-thrombotic indexes. Our results provide the first immunological data possibly related to the use of umbilical cord-derived MSCs in severe COVID-19 context.
| S-EPMC8170427 | biostudies-literature
Project description:Studies of mesenchymal stem (or stromal) cells (MSCs) have moved from bedside to bench and back again. The stromal cells or fibroblasts are found in all tissues and participate in building the extracellular matrix (ECM). Bone marrow (BM)-derived MSCs have been studied for more than 50 years and have multiple roles. They function as stem cells and give rise to bone, cartilage, and fat in the BM (these are stem cells); support hematopoiesis (pericytes); and participate in sensing environmental changes and balancing pro- and anti-inflammatory conditions. In disease states, they migrate to sites of injury and release cytokines, hormones, nucleic acids depending on the microenvironment they find. Clinicians have begun to exploit these properties of BM, adipose tissue, and umbilical cord MSCs because they are easy to harvest and expand in culture. In this review, I describe the uses to which MSCs have been put, list ongoing clinical trials by organ system, and outline how MSCs are thought to regulate the innate and adaptive immune systems. I will discuss some of the reasons why clinical applications are still lacking. Much more work will have to be done to find the sources, doses, and culture conditions needed to exploit MSCs optimally and learn their healing potential. They are worth the effort.
| S-EPMC8929448 | biostudies-literature
Project description:BACKGROUND:Senolytic drugs are thought to target senescent cells and might thereby rejuvenate tissues. In fact, such compounds were suggested to increase health and lifespan in various murine aging models. So far, effects of senolytic drugs have not been analysed during replicative senescence of human mesenchymal stromal cells (MSCs). METHODS:In this study, we tested four potentially senolytic drugs: ABT-263 (navitoclax), quercetin, nicotinamide riboside, and danazol. The effects of these compounds were analysed during long-term expansion of MSCs, until replicative senescence. Furthermore, we determined the effect on molecular markers for replicative senescence, such as senescence-associated beta-galactosidase staining (SA-β-gal), telomere attrition, and senescence-associated DNA methylation changes. RESULTS:Co-culture experiments of fluorescently labelled early and late passages revealed that particularly ABT-263 had a significant but moderate senolytic effect. This was in line with reduced SA-β-gal staining in senescent MSCs upon treatment with ABT-263. However, none of the drugs had significant effects on the maximum number of population doublings, telomere length, or epigenetic senescence predictions. CONCLUSIONS:Of the four tested drugs, only ABT-263 revealed a senolytic effect in human MSCs-and even treatment with this compound did not rejuvenate MSCs with regard to telomere length or epigenetic senescence signature. It will be important to identify more potent senolytic drugs to meet the high hopes for regenerative medicine.
| S-EPMC5907463 | biostudies-literature
Project description:Mesenchymal stem/stromal cells (MSCs) are multipotent cells residing in the stromal tissues of the body and capable of promoting tissue repair and attenuating inflammatory processes through their immunomodulatory properties. Preclinical and clinical observations revealed that not only direct intercellular communication mediates MSC properties; in fact, a pivotal role is also played by the release of soluble and bioactive factors, such as cytokines, growth factor and extracellular vesicles (EVs). EVs are membrane-coated vesicles containing a large variety of bioactive molecules, including lipids, proteins, and nucleic acids, such as RNA. EVs release their contents into target cells, thus influencing cell fate through the control of intracellular processes. In addition, MSC-derived EVs can mediate modulatory effects toward different effector cells belonging to both innate and adaptive immunity. In this review, we will discuss the literature data concerning MSC-derived EVs, including the current standardized methods for their isolation and characterization, the mechanisms supporting their immunoregulatory properties, and their potential clinical application as alternative to MSC-based therapy for inflammatory reactions, such as graft-versus-host disease (GvHD).
| S-EPMC7677193 | biostudies-literature
Project description:ObjectivesTo evaluate the quality of preclinical evidence for mesenchymal stromal cell (MSC) treatment of ischemic stroke, determine effect size of MSC therapy, and identify clinical measures that correlate with differences in MSC effects.MethodsA literature search identified studies of MSCs in animal models of cerebral ischemia. For each, a Quality Score was derived, and effect size of MSCs was determined for the most common behavioral and histologic endpoints.ResultsOf 46 studies, 44 reported that MSCs significantly improved outcome. The median Quality Score was 5.5 (of 10). The median effect size was 1.78 for modified Neurological Severity Score, 1.73 for the adhesive removal test, 1.02 for the rotarod test, and 0.93 for infarct volume reduction. Quality Score correlated significantly and positively with effect size for the modified Neurological Severity Score. Effect sizes varied significantly with clinical measures such as administration route (intracerebral > intra-arterial > IV, although effect size for IV was nonetheless very large at 1.55) and species receiving MSCs (primate > rat > mouse). Because many MSC mechanisms are restorative, analyses were repeated examining only the 36 preclinical studies administering MSCs ? 24 hours poststroke; results were overall very similar.ConclusionsIn preclinical studies, MSCs have consistently improved multiple outcome measures, with very large effect sizes. Results were robust across species studied, administration route, species of MSC origin, timing, degree of immunogenicity, and dose, and in the presence of comorbidities. In contrast to meta-analyses of preclinical data for other stroke therapies, higher-quality MSC preclinical studies were associated with larger behavioral gains. These findings support the utility of further studies to translate MSCs in the treatment of ischemic stroke in humans.
| S-EPMC4001201 | biostudies-literature
Project description:BackgroundMesenchymal stromal cells (MSC) have shown promising results in the treatment of tendinopathy in equine medicine, making this therapeutic approach seem favorable for translation to human medicine. Having demonstrated that MSC engraft within the tendon lesions after local injection in an equine model, we hypothesized that they would improve tendon healing superior to serum injection alone.MethodsQuadrilateral tendon lesions were induced in six horses by mechanical tissue disruption combined with collagenase application 3 weeks before treatment. Adipose-derived MSC suspended in serum or serum alone were then injected intralesionally. Clinical examinations, ultrasound and magnetic resonance imaging were performed over 24 weeks. Tendon biopsies for histological assessment were taken from the hindlimbs 3 weeks after treatment. Horses were sacrificed after 24 weeks and forelimb tendons were subjected to macroscopic and histological examination as well as analysis of musculoskeletal marker expression.ResultsTendons injected with MSC showed a transient increase in inflammation and lesion size, as indicated by clinical and imaging parameters between week 3 and 6 (p < 0.05). Thereafter, symptoms decreased in both groups and, except that in MSC-treated tendons, mean lesion signal intensity as seen in T2w magnetic resonance imaging and cellularity as seen in the histology (p < 0.05) were lower, no major differences could be found at week 24.ConclusionsThese data suggest that MSC have influenced the inflammatory reaction in a way not described in tendinopathy studies before. However, at the endpoint of the current study, 24 weeks after treatment, no distinct improvement was observed in MSC-treated tendons compared to the serum-injected controls. Future studies are necessary to elucidate whether and under which conditions MSC are beneficial for tendon healing before translation into human medicine.
| S-EPMC6052633 | biostudies-literature