scholarly journals Modulation of Immunoregulatory Properties of Mesenchymal Stromal Cells by Toll-Like Receptors: Potential Applications on GVHD

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Bruno Sangiorgi ◽  
Rodrigo Alexandre Panepucci
Keyword(s):  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Opportunistic Infections ◽  
Inflammatory Factors ◽  
Human Mscs ◽  
Toll Like Receptors ◽  
Potential Applications ◽  
Potential Applicability ◽  
Source Tissue ◽  
Molecular Patterns

In the last decade, the immunomodulatory properties of mesenchymal stromal cells (MSCs) have attracted a lot of attention, due to their potential applicability in the treatment of graft-versus-host disease (GVHD), a condition frequently associated with opportunistic infections. The present review addresses how Pathogen-Associated Molecular Patterns (PAMPS) modulate the immunosuppressive phenotype of human MSCs by signaling through Toll-like receptors (TLRs). Overall, we observed that regardless of the source tissue, human MSCs express TLR2, TLR3, TLR4, and TLR9. Stimulation of distinct TLRs on MSCs elicits distinct inflammatory signaling pathways, differentially influencing the expression of inflammatory factors and the ability of MSCs to suppress the proliferation of immune system cells. The capacity to enhance the immunosuppressive phenotype of MSCs through TLRs stimulation might be properly elucidated in order to improve the MSC-based immunotherapy against GVHD.

Regulation of TLR Expression and Activation in Human Mesenchymal Stromal Cells by IFN-a, IFN-g and TNF-a.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1790-1790
Author(s):  
Moïra François ◽  
Raphaëlle Romieu-Mourez ◽  
Marie-Noëlle Boivin ◽  
Jacques Galipeau
Keyword(s):  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Poly I:C ◽  
Marginal Effect ◽  
Human Mscs ◽  
Regulation Of Expression ◽  
Mesenchymal Progenitors ◽  
Polycytidylic Acid ◽  
Antigen Presenting ◽  
Molecular Patterns

Abstract Members of the toll-like receptor (TLR) family bind to pathogen-associated molecular patterns and subsequently induce the activation of the innate and adaptive immune responses. We investigated here the expression and role of TLRs in mesenchymal stromal cells (MSC), which are bone marrow-derived mesenchymal progenitors with recently described antigen presenting cell (APC) properties [Stagg et al, Blood (March 2006), Romieu et al., JI (in press)]. We observed that human MSCs express basal levels of TLR3 and TLR4, and these responded to their respective ligands, e.g. polycytidylic acid (poly I:C) or lipopolysaccharide (LPS), by the production of IL-6, IL-8 and IL-1b but not of active IL-12 p70 dimer. Exposure of MSCs to TNF-a increased the expression of TLR2 and TLR4 while IFN-a strongly upregulated TLR3 expression. By contrast, IFN-g had only a marginal effect on the expression of any TLR. IFN-a and poly I:C, as well as IFN-g and poly I:C or LPS were observed to work in synergy for the up-regulation of expression of several cytokines or inflammatory mediators, such as IL-12 p35 (IL-12A), TNF-a, RANTES, TRAIL, IFN-b and NOS2A in MSC. In contrast, none of these treatments induced the upregulation of IL-12 p40 (IL-12B), which may explain the lower levels of IL-12 p70 produced in MSCs compared to primary macrophages. Since c-Rel/p50 NF-kB dimers as well as IFN-induced IRF-1 were shown to control IL-12B and/or IL12A promoters, respectively, we next investigated expression of these transcription factors in MSCs. Results showed that MSC expressed the ubiquitous RelA NF-kB subunit but displayed significantly lower expression of c-Rel compared to macrophages. IRF-1 was upregulated following treatments with IFN-g or, to a lesser extent, with IFN-a. Therefore, the lower levels of IL-12 p70 seen in MSCs compared to macrophages may be explained by the absence of c-Rel in MSCs, which hinders the upregulation of IL-12A and IL-12B after exposure to single TLR ligands. However, the induction of IRF-1 by IFN-g or IFN-a may explain the synergistic effect observed in the upregulation of IL-12A in MSC treated with IFN-g or IFN-a and TLR ligands. In conclusion, TLR expression in human MSCs plays a role in their immune activation, although the outcome of this activation is different from the result of macrophage activation by TLR.

Evaluation of Potential Application of Wharton’s Jelly-Derived Human Mesenchymal Stromal Cells and its Conditioned Media for Dermal Regeneration using Rat Wound Healing Model

2021 ◽  
pp. 1-14
Author(s):  
Caroline Mathen ◽  
Mrunal Ghag Sawant ◽  
Raghubansh Gupta ◽  
Wilfrid Dsouza ◽  
Shilpa G. Krishna
Keyword(s):  
Wound Healing ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Therapeutic Potential ◽  
Wound Care ◽  
Free Cell ◽  
Conditioned Media ◽  
Human Umbilical Cord ◽  
Human Mscs ◽  
Wound Model

Mesenchymal stromal cells and the derived conditioned media represent an area of tremendous medical interest and, among other clinical applications, are currently being extensively explored for wound healing. The aim of this study was to comparatively evaluate the wound healing potential of xeno-free human umbilical cord-derived mesenchymal stromal cells (MSCs) and the conditioned media (CM) in a full-thickness excision wound model in rats. The evaluation parameters included rate of wound healing, serum cytokine analyses, collagen content, histopathology, and hyperspectral imaging as an independent qualitative and quantitative tool. Both the cell-based and cell-free approaches scored better in lower inflammation, as evidenced in lower IL-10 and stable IL-6 levels, and improved rate of wound healing (<i>p</i> &#x3c; 0.0001). More importantly, no adverse reaction or rejection was observed although human MSCs and CM were used in a xenogeneic model. The presence of hFGF, hHGF, hGCSF, hIL-1Ra, hVEGF, and hIL-6 in the secretome may elucidate the regenerative potential of the xeno-free cell-based and cell-free approaches which have translational value for advanced wound care. The results revealed the therapeutic potential of both the cell-based and cell-free approaches for wound healing.

scholarly journals The oncometabolite R-2-hydroxyglutarate dysregulates the differentiation of human mesenchymal stromal cells via inducing DNA hypermethylation

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Lizhen Liu ◽  
Kaimin Hu ◽  
Jingjing Feng ◽  
Huafang Wang ◽  
Shan Fu ◽  
...  
Keyword(s):  
Osteogenic Differentiation ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Chondrogenic Differentiation ◽  
Cell Counting ◽  
Human Mscs ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Dna Hypermethylation ◽  
Cartilaginous Tumors

Abstract Background Isocitrate dehydrogenase (IDH1/2) gene mutations are the most frequently observed mutations in cartilaginous tumors. The mutant IDH causes elevation in the levels of R-enantiomer of 2-hydroxylglutarate (R-2HG). Mesenchymal stromal cells (MSCs) are reasonable precursor cell candidates of cartilaginous tumors. This study aimed to investigate the effect of oncometabolite R-2HG on MSCs. Methods Human bone marrow MSCs treated with or without R-2HG at concentrations 0.1 to 1.5 mM were used for experiments. Cell Counting Kit-8 was used to detect the proliferation of MSCs. To determine the effects of R-2HG on MSC differentiation, cells were cultured in osteogenic, chondrogenic and adipogenic medium. Specific staining approaches were performed and differentiation-related genes were quantified. Furthermore, DNA methylation status was explored by Illumina array-based arrays. Real-time PCR was applied to examine the signaling component mRNAs involved in. Results R-2HG showed no influence on the proliferation of human MSCs. R-2HG blocked osteogenic differentiation, whereas promoted adipogenic differentiation of MSCs in a dose-dependent manner. R-2HG inhibited chondrogenic differentiation of MSCs, but increased the expression of genes related to chondrocyte hypertrophy in a lower concentration (1.0 mM). Moreover, R-2HG induced a pronounced DNA hypermethylation state of MSC. R-2HG also improved promotor methylation of lineage-specific genes during osteogenic and chondrogenic differentiation. In addition, R-2HG induced hypermethylation and decreased the mRNA levels of SHH, GLI1and GLI2, indicating Sonic Hedgehog (Shh) signaling inhibition. Conclusions The oncometabolite R-2HG dysregulated the chondrogenic and osteogenic differentiation of MSCs possibly via induction of DNA hypermethylation, improving the role of R-2HG in cartilaginous tumor development.

Comparative Study of Ceramics Structure for Culturing Human Mesenchymal Stromal Cells

2007 ◽  
Vol 361-363 ◽  
pp. 1067-1070 ◽  
Author(s):  
Asako Matsushima ◽  
Noriko Kotobuki ◽  
Mika Tadokoro ◽  
Hajime Ohgushi
Keyword(s):  
Bone Tissue ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Cell Attachment ◽  
Osteoblastic Differentiation ◽  
Human Mscs ◽  
Osteogenic Cells ◽  
Human Mesenchymal Stromal Cells ◽  
Viable Cells ◽  
Different Types

Hydroxyapatite (HA) ceramics together with various kinds of osteogenic cells have been used in bone tissue engineering. It is well known that the ceramics structure and composition affect cell proliferation / differentiation. In this study, three different types of HA ceramics were used to investigate initial cell attachment followed by osteoblastic differentiation of human mesenchymal stromal cells (MSCs). The results indicated that micro-pore affected the cell attachment and porosity (pore diameter and inter-pore connection) was the key to allow spacious distribution of the viable cells in the ceramics. This study also confirmed that surface pore areas of HA ceramics support the differentiation of human MSCs and thus the ceramics have the capability to regenerate damaged bone tissue.

scholarly journals Characterization and Comparison of Human and Ovine Mesenchymal Stromal Cells from Three Corresponding Sources

2020 ◽  
Vol 21 (7) ◽  
pp. 2310 ◽  
Author(s):  
El-Mustapha Haddouti ◽  
Thomas M. Randau ◽  
Cäcilia Hilgers ◽  
Werner Masson ◽  
Klaus J. Walgenbach ◽  
...  
Keyword(s):  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Therapeutic Option ◽  
Large Animal Model ◽  
Osteogenic Potential ◽  
Large Animal ◽  
Human Mscs ◽  
Mineralization Process ◽  
Hla Dr ◽  
Different Sources

Currently, there is an increasing focus on mesenchymal stromal cells (MSC) as therapeutic option in bone pathologies as well as in general regenerative medicine. Although human MSCs have been extensively characterized and standardized, ovine MSCs are poorly understood. This limitation hampers clinical progress, as sheep are an excellent large animal model for orthopedic studies. Our report describes a direct comparison of human and ovine MSCs from three corresponding sources under the same conditions. All MSCs presented solid growth behavior and potent immunomodulatory capacities. Additionally, we were able to identify common positive (CD29, CD44, CD73, CD90, CD105, CD166) and negative (CD14, CD34, CD45, HLA-DR) surface markers. Although both human and ovine MSCs showed strong osteogenic potential, direct comparison revealed a slower mineralization process in ovine MSCs. Regarding gene expression level, both human and ovine MSCs presented a comparable up-regulation of Runx2 and a trend toward down-regulation of Col1A during osteogenic differentiation. In summary, this side by side comparison defined phenotypic similarities and differences of human and ovine MSCs from three different sources, thereby contributing to a better characterization and standardization of ovine MSCs. The key findings shown in this report demonstrate the utility of ovine MSCs in preclinical studies for MSC-based therapies.

scholarly journals Quantitative Efficacy and Fate of Mesenchymal Stromal Cells Targeted to Cardiac Sites by Radiofrequency Catheter Ablation

2020 ◽  
Vol 29 ◽  
pp. 096368972091423
Author(s):  
Rizwan Malik ◽  
Fabrice F. Darche ◽  
Rasmus Rivinius ◽  
Anja Seckinger ◽  
Ulf Krause ◽  
...  
Keyword(s):  
Stem Cell ◽  
Catheter Ablation ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Radiofrequency Catheter Ablation ◽  
Functional Integration ◽  
Right Atrial ◽  
Blue Staining ◽  
Large Animal ◽  
Human Mscs

Engraftment and functional integration of stem cells or stem cell-derived cells within cardiac tissue is an important prerequisite for cell replacement therapy aiming at the treatment of heart disease. Recently, a novel intravenous approach for application of mesenchymal stromal cells (MSCs) to cardiac sites has been established using radiofrequency catheter ablation (RFCA)-guided targeting, bypassing the need for open chest surgery or direct myocardial cell injection. However, little is known about the quantitative efficacy and longevity of this strategy. We performed selective power-controlled RFCA with eight ablation pulses (30 W, 60 s each) to induce heat-mediated lesions at the right atrial appendices (RAAs) of pigs. Different concentrations of human bone marrow-derived MSCs (105 to 1.6 × 106 cells/kg bodyweight) labeled with superparamagnetic iron oxide (SPIO) particles were infused intravenously in nine pigs one d after RFCA treatment and hearts were explanted 8 d later to quantify the number of engrafted cells. Prussian blue staining revealed high numbers of SPIO-labeled cells in areas surrounding the RFCA-induced lesions. Cell numbers were evaluated by quantitative real-time polymerase chain reaction using specific primers for human MSCs (hMSCs), which indicated that up to 106 hMSCs, corresponding to ∼3.9% of the systemically applied human cells, engrafted within the RAAs of RFCA-treated pigs. Of note, infused hMSCs were observed in nontargeted organs, as well, but appeared at very low concentrations. To assess long-term deposition of MSCs, RAAs of three pigs were analyzed after 6 months, which revealed few persisting hMSCs at targeted sites. RFCA-mediated targeting of MSCs provides a novel minimal invasive strategy for cardiac stem cell engraftment. Qualitative and quantitative results of our large animal experiments indicate an efficient guidance of MSCs to selected cardiac regions, although only few cells remained at targeted sites 6 mo after cell transplantation.

scholarly journals Preconditioning in an Inflammatory Milieu Augments the Immunotherapeutic Function of Mesenchymal Stromal Cells

Cells ◽  
2019 ◽  
Vol 8 (5) ◽  
pp. 462 ◽  
Author(s):  
Luis A. Rodriguez ◽  
Arezoo Mohammadipoor ◽  
Lucero Alvarado ◽  
Robin M. Kamucheka ◽  
Amber M. Asher ◽  
...  
Keyword(s):  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Comprehensive Evaluation ◽  
Multipotent Mesenchymal Stromal Cells ◽  
Human Mscs ◽  
Post Injury ◽  
Anti Inflammatory ◽  
And Function ◽  
Inflammatory Milieu

Multipotent mesenchymal stromal cells (MSCs) have emerged as potent therapeutic agents for multiple indications. However, recent evidence indicates that MSC function is compromised in the physiological post-injury milieu. In this study, bone marrow (BM)- and adipose-derived (AD)-MSCs were preconditioned in hypoxia with or without inflammatory mediators to potentiate their immunotherapeutic function in preparation for in vivo delivery. Human MSCs were cultured for 48 h in either normoxia (21% O2) or hypoxia (2% O2) with or without the addition of Cytomix, thus creating 4 groups: (1) normoxia (21%); (2) Cytomix-normoxia (+21%); (3) hypoxia (2%); and (4) Cytomix-hypoxia (+2%). The 4 MSC groups were subjected to comprehensive evaluation of their characteristics and function. Preconditioning did not alter common MSC surface markers; nonetheless, Cytomix treatment triggered an increase in tissue factor (TF) expression. Moreover, the BM-MSCs and AD-MSCs from the +2% group were not able to differentiate to chondrocytes and osteoblasts, respectively. Following Cytomix preconditioning, the metabolism of MSCs was significantly increased while viability was decreased in AD-MSCs, but not in BM-MSCs. MSCs from both tissues showed a significant upregulation of key anti-inflammatory genes, increased secretion of IL-1 receptor antagonist (RA), and enhanced suppression of T-cell proliferation following the Cytomix treatment. Similarly, following a lipopolysaccharide challenge, the Cytomix-treated MSCs suppressed TNF-α secretion, while promoting the production of IL-10 and IL-1RA. These preconditioning approaches facilitate the production of MSCs with robust anti-inflammatory properties. AD-MSCs preconditioned with Cytomix under normoxia appear to be the most promising therapeutic candidates; however, safety concerns, such as thrombogenic disposition of cells due to TF expression, should be carefully considered prior to clinical translation.

scholarly journals Deciphering Master Gene Regulators and Associated Networks of Human Mesenchymal Stromal Cells

Biomolecules ◽  
2020 ◽  
Vol 10 (4) ◽  
pp. 557
Author(s):  
Elena Sánchez-Luis ◽  
Andrea Joaquín-García ◽  
Francisco J. Campos-Laborie ◽  
Fermín Sánchez-Guijo ◽  
Javier De las Rivas
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Transcription Factors ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Cell Structure ◽  
Regulatory Gene ◽  
Human Mscs ◽  
Protein Activity ◽  
Hematopoietic Stem

Mesenchymal Stromal Cells (MSC) are multipotent cells characterized by self-renewal, multilineage differentiation, and immunomodulatory properties. To obtain a gene regulatory profile of human MSCs, we generated a compendium of more than two hundred cell samples with genome-wide expression data, including a homogeneous set of 93 samples of five related primary cell types: bone marrow mesenchymal stem cells (BM-MSC), hematopoietic stem cells (HSC), lymphocytes (LYM), fibroblasts (FIB), and osteoblasts (OSTB). All these samples were integrated to generate a regulatory gene network using the algorithm ARACNe (Algorithm for the Reconstruction of Accurate Cellular Networks; based on mutual information), that finds regulons (groups of target genes regulated by transcription factors) and regulators (i.e., transcription factors, TFs). Furtherly, the algorithm VIPER (Algorithm for Virtual Inference of Protein-activity by Enriched Regulon analysis) was used to inference protein activity and to identify the most significant TF regulators, which control the expression profile of the studied cells. Applying these algorithms, a footprint of candidate master regulators of BM-MSCs was defined, including the genes EPAS1, NFE2L1, SNAI2, STAB2, TEAD1, and TULP3, that presented consistent upregulation and hypomethylation in BM-MSCs. These TFs regulate the activation of the genes in the bone marrow MSC lineage and are involved in development, morphogenesis, cell differentiation, regulation of cell adhesion, and cell structure.

scholarly journals CD14 dictates differential activation of mesenchymal stromal cells through AKT, NF-κB and P38 signals

2019 ◽  
Vol 39 (7) ◽  
Author(s):  
Menghui Jiang ◽  
Tianlin Gao ◽  
Yuansheng Liu ◽  
Xue Cao ◽  
Yanting Li ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Expression Patterns ◽  
Mrna Level ◽  
Human Mscs ◽  
Differentiation Potential ◽  
Tlr4 Signaling ◽  
Tlr4 Signaling Pathway ◽  
Different Sources

Abstract Mesenchymal stromal cells (MSCs) widely exist in many tissues and have multiple differentiation potential and immunomodulatory capacities. Recently, MSCs have become promising tools for the treatment of various degenerative disorders and autoimmune diseases. The properties of MSCs could be modified in different microenvironments. Thus, it is important to explore the factors controlling MSC function. The presence of Toll-like receptors (TLRs) in MSCs was demonstrated according to previous studies. Consistently, we also illustrated the expression of TLRs in both murine and human MSCs, and displayed that the expression patterns of TLRs in MSCs from different sources. Furthermore, we explored the role of TLR and TLR signaling pathway in MSCs. Interestingly, activation of TLR4-induced expression of cytokines and some specific genes in MSCs. However, MSCs retained much lower mRNA level compared with macrophages. We explored the expression of CD14 in MSCs from different sources, which played a vital role in TLR4 signaling pathway, and found that MSCs are almost negative for CD14. Moreover, only partial activation of TLR4 signaling pathway was observed in MSCs, with no activation of AKT, NF-κB and P38. Here, in the study we defined TLR expression, function and activation in MSCs, which is critical for designing MSC-based therapies.

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