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NFAT signalling in human mesenchymal stromal cells affects extracellular matrix metabolism and anti-fungal immune responses

ABSTRACT: Mesenchymal stromal cells (MSCs) combined with calcineurin-NFAT (CN-NFAT) inhibitors are being tested as a treatment for graft versus host disease (GvHD). The immunosuppressive properties of MSCs seem beneficial; however, their response during fungal infection, which is an important cause of mortality in GvHD patients, is unknown. We report that MSCs phagocytose the fungal component zymosan, resulting in phosphorylation of Syk kinase, increase in cytosolic calcium levels and ultimately, in NFAT1 nuclear translocation. RNA-sequencing analysis of zymosan-treated MSCs showed that CN-NFAT inhibition affects extracellular matrix (ECM) genes, but not cytokine expression that is under the control of the NF-κB pathway. When co-culturing MSCs or decellularized MSC-ECM with human peripheral blood mononuclear cells (PBMCs), selective NFAT inhibition in MSCs decreased cytokine expression by PBMCs. These findings reveal a dual mechanism underlying the MSC response to zymosan: while NF-κB directly controls inflammatory cytokine expression, NFAT impacts immune-cell functions by regulating ECM remodelling.

ORGANISM(S): Homo sapiens

PROVIDER: GSE157981 | GEO | 2021/06/14

REPOSITORIES: GEO

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Independent human mesenchymal stromal cell-derived extracellular vesicle preparations differentially attenuate symptoms in an advanced murine Graft-versus-Host-Disease model

Project description:Extracellular vesicles (EVs) harvested from conditioned media of human mesenchymal stromal cells (MSCs) suppress acute inflammation in various disease models and promote regeneration of damaged tissues. Following successful treatment of an acute steroid-refractory Graft-versus-Host disease (GvHD) patient with EVs prepared from conditioned media of human bone marrow-derived MSCs, we focus on improving the MSC-EV production for the clinical application. Independent MSC-EV preparations all produced according to a standardized procedure, reveal broad immunomodulatory differences. Only a proportion of our MSC-EV products effectively modulate immune responses in a multi-donor mixed lymphocyte reaction (mdMLR) assay. To explore the relevance of such differences, we have established an optimized mouse GvHD model. The functional testing of selected MSC-EV preparations demonstrate that MSC-EV preparations revealing immunomodulatory capabilities in the mdMLR assay also effectively suppress GvHD symptoms in this model. In contrast, MSC-EV preparations, lacking such in vitro activities, also fail to modulate GvHD symptoms in vivo. Searching for differences of the active and inactive MSC-EV preparations, we failed to identify concrete proteins or miRNAs that could serve as surrogate markers. Thus, standardized MSC-EV production strategies may not be sufficient to warrant manufacturing of MSC-EV products with reproducible qualities. Consequently, given this functional heterogeneity, every individual MSC-EV preparation considered for the clinical application should be evaluated for its therapeutic potency prior to administration to patients. Here, we qualified the mdMLR assay for such analyses.

2023-06-12 | PXD032744 | Pride

Transcription profiling of mouse MyD88-deficient bone marrow-derived macrophages treated with Zymosan

Project description:Innate immune pattern recognition receptors play critical roles in pathogen detection and initiation of antimicrobial responses. We and others have previously demonstrated the importance of the beta-glucan receptor Dectin-1 in the recognition of pathogenic fungi by macrophages and dendritic cells, and have elucidated some of the mechanisms by which Dectin-1 signals to coordinate the antifungal response. While Dectin-1 signals alone are sufficient to trigger phagocytosis and Src-Syk-mediated induction of antimicrobial reactive oxygen species, collaboration with Toll-like receptor (TLR)2 signaling enhances NF-kB activation and regulates cytokine production. In this study we demonstrate that Dectin-1 signaling can also directly modulate gene expression via activation of nuclear transcription of activated T cells (NFAT) transcription factors. Dectin-1 ligation by zymosan particles or live Candida albicans yeast triggers NFAT activation in macrophages and dendritic cells. Dectin-1-triggered NFAT activation plays a role in the induction of Egr2 and Egr3 transcription factors, and cyclooxygenase 2 (Cox-2). Furthermore, we show that NFAT activation regulates IL-2, IL-10 and IL-12 p70 production by zymosan-stimulated dendritic cells. These data establish NFAT activation in myeloid cells as a novel mechanism of regulation of the innate antimicrobial response. Experiment Overall Design: Bone marrow-derived macrophages deficient in MyD88 were stimulated with zymosan, and total RNA was extracted 120 minutes after stimulation for comparison to macrophages grown under the same conditions, but not stimulated.

2008-06-14 | E-GEOD-6376 | biostudies-arrayexpress

Human osteoblast-derived extracellular matrix with high homology to human bone proteome is osteopromotive for mesenchymal stromal cells

Project description:Efficient osteogenic differentiation of mesenchymal stem cells (MSCs) is crucial to accelerate bone formation. In this context, the use of extracellular matrix (ECM) as natural 3D-framework mimicking in vivo tissue architecture is of interest. The aim of this study was to generate a devitalized human osteogenic MSC-derived ECM and to investigate its impact on MSC osteogenic differentiation to improve MSC properties in bone regeneration. The devitalized ECM significantly enhanced MSC adhesion and proliferation. Osteogenic differentiation and mineralization of MSCs on the ECM was quicker than in standard conditions. The presence of ECM promoted in vivo bone formation by MSCs in a mouse model of ectopic-calcification. We analyzed the ECM composition by mass spectrometry, detecting 846 proteins. Of these, 473 proteins were shared with the human bone proteome we previously described, demonstrating high homology to an in vivo microenvironment. Bioinformatic analysis of the 846 proteins showed involvement in adhesion and osteogenic differentiation, confirming the ECM composition as key modulator of MSC behaviour. In addition to known ECM-components, proteomic analysis revealed novel ECM functions, which could improve culture conditions. In summary, this study provides a simplified method to obtain an in vitro MSC-derived ECM that enhances osteogenic differentiation, and could be applied as natural biomaterial to accelerate bone regeneration.

2022-02-24 | PXD006865 | Pride

miR204-containing exosome ameliorates GVHD-associated dry eye disease

Project description:The graft-versus-host disease (GVHD) associated dry eye disease usually leads to refractory pain and visual impairment with limited treatments currently. Here we found exosome derived from mesenchymal stromal cell (MSC-exo) administered as eye drops significantly alleviates GVHD-associated dry eye disease in human and mouse models. To find out the essential elements during exosome treatment, we performed miRNA sequencing of exosomes derived from MSCs and L929 cells, and identified miR-204 in MSC-exo benefited the recovery of dry eye, which targeted IL-6/IL-6R/Stat3 signaling. Blockade of miR-204 abolished the therapeutic effect of MSC-exo while miR-204 overexpression from L929-exo markedly attenuates dry eye. Thus MSC-exo eye drops are efficacious in treating GVHD-associated dry eye and highlight miR-204 as a potential therapeutic agent.

2022-01-19 | GSE166585 | GEO

Mesenchymal stem cell integrin-associated complexes

Project description:The composition and stiffness of the extracellular matrix (ECM) environment that surrounds Multipotent mesenchymal stem cells (MSCs) stem cells dictates transcriptional programming, thereby affecting stem cell lineage decision-making. Cells sense force between themselves and their microenvironment controlling the capability of MSCs to differentiate into adipocytes, osteocytes and chondrocytes. Force sensing is transmitted by integrin receptors and their associated adhesion signalling complexes. To identify regulators of MSC force sensing we sought to catalogue MSC adhesion complex composition. Therefore we isolated integrin-associated adhesion complexes formed in MSCs plated on the ECM ligand fibronectin. We identifed proteins using mass spectrometry that define a MSC specific subset of adhesion complex proteins consisting of key linkages to the actin cytoskeleton together with integrin signalling and force sensing components.

2016-07-20 | MSV000079956 | MassIVE

Mesenchymal stem cell integrin-associated complexes

2015-07-20 | PXD001809 | Pride

RhoA Determines Lineage Fate of MSCs by Modulating CTGF-VEGF Complex in Extracellular Matrix

Project description:Mesenchymal stem cells (MSCs) participate in the repair/remodeling of many tissues, where MSCs commit to different lineages dependent on the cues in the local microenvironment. Here we show that TGFβ-activated RhoA/ROCK functions as a molecular switch regarding the fate of MSCs in arterial repair/remodeling after injury. MSCs differentiate into myofibroblasts when RhoA/ROCK is turned on, endothelial cells when turned off. The former is pathophysiologic resulting in intimal hyperplasia, whereas the latter is physiological leading to endothelial repair. Further analysis revealed that MSC RhoA activation promotes formation of an extracellular matrix (ECM) complex consisting of connective tissue growth factor (CTGF) and vascular endothelial growth factor (VEGF). Inactivation of RhoA/ROCK in MSCs induces matrix metalloproteinase-3-mediated CTGF cleavage, resulting in VEGF release and MSC endothelial differentiation. Our findings uncover a novel mechanism by which cell-ECM interactions determine stem cell lineage specificity and offer additional molecular targets to manipulate MSC-involved tissue repair/regeneration.

2016-03-01 | GSE73557 | GEO

Improved Efficacy of MSCs stably expressing CXCR4 and IL-10 in a xenogeneic Graft versus Host Disease Mouse Model

Project description:Previous clinical trials have shown that mesenchymal stromal cells (MSCs) can modulate graft versus host disease (GvHD) after allogeneic hematopoietic transplantation, although with variable efficacy. To improve the anti-GvHD effect of these cells, adipose tissue derived-human MSCs (Ad-MSCs) were transduced with a lentiviral vector conferring stable expression of CXCR4, a molecule involved in cell migration to inflamed sites, and IL-10, a cytokine with potent anti-inflammatory properties. In vitro experiments showed that the expression of these molecules in Ad-MSCs (named CXCR4-IL10-MSCs) efficiently enhanced their migration towards SDF‐1α and also improved their immunomodulatory properties compared to unmodified Ad‐MSCs (WT‐MSCs). Moreover, using a humanized GvHD mouse model, CXCR4-IL10-MSCs showed improved therapeutic effects, which were confirmed by histopathologic analysis in the target organs. Additionally, compared to WT-MSCs, CXCR4-IL10-MSCs induced a more marked reduction in the number of pro-inflammatory Th1 and Th17 cells, a higher polarization towards an anti-inflammatory T cell profile (CD3+-IL10+ cells), and increased the number of regulatory T and B cells. Our in vitro and in vivo studies strongly suggest that CXCR4-IL10-MSCs should constitute an important new generation of MSCs for the treatment of GvHD in patients transplanted with allogeneic hematopoietic grafts.

2023-01-25 | GSE223390 | GEO

Quantitative proteomics analysis of different sources of hMSCs

Project description:Mesenchymal stem cells (MSCs) are an attractive therapeutic tool for tissue engineering and re-generative medicine due to their regenerative and trophic properties. The best-known and most widely used are bone marrow MSCs, but they are now being harvested and developed from a wide range of adult and perinatal tissues. MSCs from different sources are believed to have dif-ferent secretion potentials and production, which may influence their therapeutic effects. To prove it, we performed a quantitative proteomic analysis based on the TMT technique of MSCs from 3 different sources: wharton’s jelly (WJ), dental pulp (DP) and bone marrow (BM). Our analysis has focused on MSC biological properties of interest for tissue engineering. We identified a total of 611 human proteins differentially expressed. WJ-MSCs shown the greatest variation compared to the other sources. WJ produced more extra-cellular matrix (ECM) proteins and ECM-affiliated proteins and appeared to more able to modulate the inflammatory and immune response. BM-MSCs display enhanced differentiation and paracrine communication capabilities. DP-MSC appeared to promote exosome production. The results obtained confirm the existence of differences between WJ, DP and BM-MSC and the need to select the MSC origin according to the therapeutic objective sought.

2023-09-20 | PXD043912 | Pride

Zymosan stimulation of MyD88-deficient bone marrow-derived macrophages

2007-01-30 | GSE6376 | GEO

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