scholarly journals Immunomodulatory Actions of Mesenchymal Stromal Cells (MSCs) in Osteoarthritis of the Knee

Osteology ◽  
2021 ◽  
Vol 1 (4) ◽  
pp. 209-224
Author(s):  
Gangireddi Suresh Babu ◽  
Yelisetty Badrish ◽  
Vinit M Oswal ◽  
Naveen Jeyaraman ◽  
Gollahalli Shivashankar Prajwal ◽  
...  
Keyword(s):  
T Cells ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Cellular Therapy ◽  
Immune Surveillance ◽  
Osteoarthritis Of The Knee ◽  
Wide Range ◽  
Monocytes And Macrophages ◽  
The Impact

Cellular therapy offers regeneration which curbs osteoarthritis of the knee. Among cellular therapies, mesenchymal stromal cells (MSCs) are readily isolated from various sources as culture expanded and unexpanded cellular population which are used as therapeutic products. Though MSCs possess a unique immunological and regulatory profile through cross-talk between MSCs and immunoregulatory cells (T cells, NK cells, dendritic cells, B cells, neutrophils, monocytes, and macrophages), they provide an immunotolerant environment when transplanted to the site of action. Immunophenotypic profile allows MSCs to escape immune surveillance and promotes their hypoimmunogenic or immune-privileged status. MSCs do not elicit a proliferative response when co-cultured with allogeneic T cells in vitro. MSCs secrete a wide range of anti-inflammatory mediators such as PGE-2, IDO, IL-1Ra, and IL-10. They also stimulate the resilient chondrogenic progenitors and enhance the chondrocyte differentiation by secretion of BMPs and TGFβ1. We highlight the various mechanisms of MSCs during tissue healing signals, their interaction with the immune system, and the impact of their lifespan in the management of osteoarthritis of the knee. A better understanding of the immunobiology of MSC renders them as an efficient therapeutic product for the management of osteoarthritis of the knee.

scholarly journals Melatonin Synergizes With Mesenchymal Stromal Cells Attenuates Chronic Allograft Vasculopathy

2021 ◽  
Vol 12 ◽  
Author(s):  
Ya-fei Qin ◽  
De-jun Kong ◽  
Hong Qin ◽  
Yang-lin Zhu ◽  
Guang-ming Li ◽  
...  
Keyword(s):  
T Cells ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Th17 Cells ◽  
Memory T Cells ◽  
Transplant Recipients ◽  
Pathological Changes ◽  
Allograft Vasculopathy

BackgroundChronic rejection characterized by chronic allograft vasculopathy (CAV) remains a major obstacle to long-term graft survival. Due to multiple complicated mechanisms involved, a novel therapy for CAV remains exploration. Although mesenchymal stromal cells (MSCs) have been ubiquitously applied to various refractory immune-related diseases, rare research makes a thorough inquiry in CAV. Meanwhile, melatonin (MT), a wide spectrum of immunomodulator, plays a non-negligible role in transplantation immunity. Here, we have investigated the synergistic effects of MT in combination with MSCs in attenuation of CAV.MethodsC57BL/6 (B6) mouse recipients receiving BALB/c mouse donor aorta transplantation have been treated with MT and/or adipose-derived MSCs. Graft pathological changes, intragraft immunocyte infiltration, splenic immune cell populations, circulating donor-specific antibodies levels, cytokine profiles were detected on post-operative day 40. The proliferation capacity of CD4+ and CD8+ T cells, populations of Th1, Th17, and Tregs were also assessed in vitro.ResultsGrafts in untreated recipients developed a typical pathological feature of CAV characterized by intimal thickening 40 days after transplantation. Compared to untreated and monotherapy groups, MT in combination with MSCs effectively ameliorated pathological changes of aorta grafts indicated by markedly decreased levels of intimal hyperplasia and the infiltration of CD4+ cells, CD8+ cells, and macrophages, but elevated infiltration of Foxp3+ cells. MT either alone or in combination with MSCs effectively inhibited the proliferation of T cells, decreased populations of Th1 and Th17 cells, but increased the proportion of Tregs in vitro. MT synergized with MSCs displayed much fewer splenic populations of CD4+ and CD8+ T cells, Th1 cells, Th17 cells, CD4+ central memory T cells (Tcm), as well as effector memory T cells (Tem) in aorta transplant recipients. In addition, the percentage of splenic Tregs was substantially increased in the combination therapy group. Furthermore, MT combined with MSCs markedly reduced serum levels of circulating allospecific IgG and IgM, as well as decreased the levels of pro-inflammatory IFN-γ, TNF-α, IL-1β, IL-6, IL-17A, and MCP-1, but increased the level of IL-10 in the recipients.ConclusionsThese data suggest that MT has synergy with MSCs to markedly attenuate CAV and provide a novel therapeutic strategy to improve the long-term allograft acceptance in transplant recipients.

scholarly journals Human Mesenchymal Stromal Cells from Adult and Neonatal Sources: A Comparative In Vitro Analysis of Their Immunosuppressive Properties Against T Cells

2014 ◽  
Vol 23 (11) ◽  
pp. 1217-1232 ◽  
Author(s):  
Marta E. Castro-Manrreza ◽  
Hector Mayani ◽  
Alberto Monroy-García ◽  
Eugenia Flores-Figueroa ◽  
Karina Chávez-Rueda ◽  
...  
Keyword(s):  
T Cells ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Human Mesenchymal Stromal Cells ◽  
Vitro Analysis ◽  
In Vitro Analysis

scholarly journals Mesenchymal stromal cells orchestrate follicular lymphoma cell niche through the CCL2-dependent recruitment and polarization of monocytes

Blood ◽  
2012 ◽  
Vol 119 (11) ◽  
pp. 2556-2567 ◽  
Author(s):  
Fabien Guilloton ◽  
Gersende Caron ◽  
Cédric Ménard ◽  
Céline Pangault ◽  
Patricia Amé-Thomas ◽  
...  
Keyword(s):  
B Cells ◽  
Cell Growth ◽  
Follicular Lymphoma ◽  
B Cell ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Specific Gene ◽  
Wide Range ◽  
Cell Niche

Abstract Accumulating evidence indicates that infiltrating stromal cells contribute directly and indirectly to tumor growth in a wide range of cancers. In follicular lymphoma (FL), malignant B cells are found admixed with heterogeneous lymphoid-like stromal cells within invaded lymph nodes and BM. In addition, mesenchymal stromal cells (MSCs) support in vitro FL B-cell survival, in particular after their engagement toward lymphoid differentiation. We show here that BM-MSCs obtained from patients with FL (FL-MSCs) display a specific gene expression profile compared with MSCs obtained from healthy age-matched donors (HD-MSCs). This FL-MSC signature is significantly enriched for genes associated with a lymphoid-like commitment. Interestingly, CCL2 could be detected at a high level within the FL-cell niche, is up-regulated in HD-MSCs by coculture with malignant B cells, and is overexpressed by FL-MSCs, in agreement with their capacity to recruit monocytes more efficiently than HD-MSCs. Moreover, FL-MSCs and macrophages cooperate to sustain malignant B-cell growth, whereas FL-MSCs drive monocyte differentiation toward a proangiogenic and lipopolysaccharide-unresponsive phenotype close to that of tumor-associated macrophages. Altogether, these results highlight the complex role of FL stromal cells that promote direct tumor B-cell growth and orchestrate FL-cell niche, thus emerging as a potential therapeutic target in this disease.

scholarly journals Mesenchymal Stromal Cells From Emphysematous Donors and Their Extracellular Vesicles Are Unable to Reverse Cardiorespiratory Dysfunction in Experimental Severe Emphysema

2021 ◽  
Vol 9 ◽  
Author(s):  
Mariana A. Antunes ◽  
Cassia L. Braga ◽  
Tainá B. Oliveira ◽  
Jamil Z. Kitoko ◽  
Ligia L. Castro ◽  
...  
Keyword(s):  
Extracellular Vesicles ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Therapeutic Potential ◽  
Chronic Obstructive ◽  
Severe Emphysema ◽  
Arginase 1 ◽  
The Impact

Although bone marrow-derived mesenchymal stromal cells (BM-MSCs) from patients with chronic obstructive pulmonary disease (COPD) appear to be phenotypically and functionally similar to BM-MSCs from healthy sources in vitro, the impact of COPD on MSC metabolism and mitochondrial function has not been evaluated. In this study, we aimed to comparatively characterize MSCs from healthy and emphysematous donors (H-MSCs and E-MSCs) in vitro and to assess the therapeutic potential of these MSCs and their extracellular vesicles (H-EVs and E-EVs) in an in vivo model of severe emphysema. For this purpose, C57BL/6 mice received intratracheal porcine pancreatic elastase once weekly for 4 weeks to induce emphysema; control animals received saline under the same protocol. Twenty-four hours after the last instillation, animals received saline, H-MSCs, E-MSCs, H-EVs, or E-EVs intravenously. In vitro characterization demonstrated that E-MSCs present downregulation of anti-inflammatory (TSG-6, VEGF, TGF-β, and HGF) and anti-oxidant (CAT, SOD, Nrf2, and GSH) genes, and their EVs had larger median diameter and lower average concentration. Compared with H-MSC, E-MSC mitochondria also exhibited a higher respiration rate, were morphologically elongated, expressed less dynamin-related protein-1, and produced more superoxide. When co-cultured with alveolar macrophages, both H-MSCs and E-MSCs induced an increase in iNOS and arginase-1 levels, but only H-MSCs and their EVs were able to enhance IL-10 levels. In vivo, emphysematous mice treated with E-MSCs or E-EVs demonstrated no amelioration in cardiorespiratory dysfunction. On the other hand, H-EVs, but not H-MSCs, were able to reduce the neutrophil count, the mean linear intercept, and IL-1β and TGF-β levels in lung tissue, as well as reduce pulmonary arterial hypertension and increase the right ventricular area in a murine model of elastase-induced severe emphysema. In conclusion, E-MSCs and E-EVs were unable to reverse cardiorespiratory dysfunction, whereas H-EVs administration was associated with a reduction in cardiovascular and respiratory damage in experimental severe emphysema.

scholarly journals The Impact of Various Culture Conditions on Human Mesenchymal Stromal Cells Metabolism

2021 ◽  
Vol 2021 ◽  
pp. 1-15
Author(s):  
Pavla Tonarova ◽  
Katerina Lochovska ◽  
Robert Pytlik ◽  
Marie Hubalek Kalbacova
Keyword(s):  
Human Serum ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Reciprocal Relationship ◽  
Heat Inactivation ◽  
High Quality ◽  
Native Form ◽  
The Impact

In vitro and in vivo analyses are closely connected, and the reciprocal relationship between the two comprises a key assumption with concern to the conducting of meaningful research. The primary purpose of in vitro analysis is to provide a solid background for in vivo and clinical study purposes. The fields of cell therapy, tissue engineering, and regenerative medicine depend upon the high quality and appropriate degree of the expansion of mesenchymal stromal cells (MSCs) under low-risk and well-defined conditions. Hence, it is necessary to determine suitable alternatives to fetal bovine serum (FBS—the laboratory gold standard) that comply with all the relevant clinical requirements and that provide the appropriate quantity of high-quality cells while preserving the required properties. Human serum (autologous and allogeneic) and blood platelet lysates and releasates are currently considered to offer promising and relatively well-accessible MSC cultivation alternatives. Our study compared the effect of heat-inactivated FBS on MSC metabolism as compared to its native form (both are used as the standard in laboratory practice) and to potential alternatives with concern to clinical application—human serum (allogeneic and autologous) or platelet releasate (PR-SRGF). The influence of the origin of the serum (fetal versus adult) was also determined. The results revealed the key impact of the heat inactivation of FBS on MSCs and the effectiveness of human sera and platelet releasates with respect to MSC behaviour (metabolic activity, proliferation, morphology, and cytokine production).

Oxygen Tension Regulates Hematopoietic Stem Cell Migration Into An in-Vitro Niche Beneath Mesenchymal Stromal Cells.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1443-1443
Author(s):  
Duohui Jing ◽  
Nael Alakel ◽  
Martin Bornhauser ◽  
Gerhard Ehninger ◽  
Rainer Ordemann
Keyword(s):  
Stem Cell ◽  
Oxygen Tension ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Conflicts Of Interest ◽  
Hematopoietic Stem ◽  
Hypoxic Conditions ◽  
Migratory Capacity ◽  
The Impact

Abstract Abstract 1443 Poster Board I-466 Background Hematopoietic stem cells (HSCs) are located mainly in the bone marrow interacting with a specific microenvironment called “stem cell niche”. The niche has been proven to be critical for stem cell regulation. Coculture with mesenchymal stromal cells (MSCs) has been used as an in vitro model to investigate the interaction between HSCs and MSCs. In our study we investigated the impact of normoxia and hypoxia on the distribution of HSC subsets with regard to their spatial localization in cocultures during ex-vivo expansion. Design and Methods Three HSC subsets are defined: (i) cells in supernatant (non-adherent cells); (ii) cells adhering on the MSC layer surface (phase-bright cells); (iii) cells beneath the MSC layer (phase-dim cells). Using pimonidazole binding we investigated the spatial distribution of hypoxic cells in various cell subsets. Cell cycle, cell division, immunophenotype and migratory capacity of the three HSC subsets under distinct oxygen tension were studied. In addition the impact of oxygen tension on HSCs via VEGF-A and SDF-1 were analyzed by ELISA and gene knockdown with siRNA. Results First we could show that phase-bright cells contained the highest proportion of cycling progenitors. In contrast, phase-dim cells divided much more slowly and retained a more immature phenotype. Next pimonidazole binding revealed that the most hypoxic area in the coculture is the compartment beneath MSC layer. Then we investigated the impact of hypoxia conditions on HSCs in cocultures. We could demonstrate that under hypoxic conditions phase-bright cells were significantly diminished and phase-dim cells were increased. Interestingly, the migratory capacity of phase-bright cells from cocultures performed under hypoxic conditions was consistently enhanced in comparison to normoxia (32.7 ±2.2.0% vs 17.6 ±2.6%, p<0.01). Surprisingly, the SDF-1 concentration was lower after hypoxic coculture (189 ±33μg/ml vs 352 ±40μg/ml, p<0.05). In contrast, the VEGF-A concentration was significantly increased compared to normoxic conditions (7.7 ±1.2ng/ml vs 4.5 ±1.0ng/ml, p<0.01). In addition we could demonstrate that the lower adhesion and higher migratory capacity of HSCs under hypoxia can be partially inversed by silencing VEGF-A with siRNA in MSCs. Conclusions Our data indicate that under our experimental conditions, the MSC surface is the dominant location where HSCs proliferate, whereas the compartment beneath the MSC layer seems to be a hypoxic niche dedicated to the maintenance of HSC stemness. The lower levels of SDF-1 in the supernatant may be explained by the increased internalization of SDF-1 by MSCs when cultured together with HSC. This hypothesis will require the concomitant analysis of protein and SDF-1 mRNA in MSC. In addition our data suggest that low oxygen tension facilitates HSC migration into the in-vitro niche provided by MSCs which preserves immaturity of HSCs and modifies the cytokine profile of MSCs. Disclosures No relevant conflicts of interest to declare.

scholarly journals Exofucosylation of Adipose Mesenchymal Stromal Cells Alters Their Secretome Profile

2020 ◽  
Vol 8 ◽  
Author(s):  
David García-Bernal ◽  
Mariano García-Arranz ◽  
Ana I. García-Guillén ◽  
Ana M. García-Hernández ◽  
Miguel Blanquer ◽  
...  
Keyword(s):  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Culture Conditions ◽  
Peripheral Tissues ◽  
Standard Culture ◽  
Anti Inflammatory ◽  
Selectin Binding ◽  
The Impact

Mesenchymal stromal cells (MSCs) constitute the cell type more frequently used in many regenerative medicine approaches due to their exclusive immunomodulatory properties, and they have been reported to mediate profound immunomodulatory effects in vivo. Nevertheless, MSCs do not express essential adhesion molecules actively involved in cell migration, a phenotypic feature that hampers their ability to home inflamed tissues following intravenous administration. In this study, we investigated whether modification by fucosylation of murine AdMSCs (mAdMSCs) creates Hematopoietic Cell E-/L-selectin Ligand, the E-selectin-binding CD44 glycoform. This cell surface glycan modification of CD44 has previously shown in preclinical studies to favor trafficking of mAdMSCs to inflamed or injured peripheral tissues. We analyzed the impact that exofucosylation could have in other innate phenotypic and functional properties of MSCs. Compared to unmodified counterparts, fucosylated mAdMSCs demonstrated higher in vitro migration, an altered secretome pattern, including increased expression and secretion of anti-inflammatory molecules, and a higher capacity to inhibit mitogen-stimulated splenocyte proliferation under standard culture conditions. Together, these findings indicate that exofucosylation could represent a suitable cell engineering strategy, not only to facilitate the in vivo MSC colonization of damaged tissues after systemic administration, but also to convert MSCs in a more potent immunomodulatory/anti-inflammatory cell therapy-based product for the treatment of a variety of autoimmune, inflammatory, and degenerative diseases.

scholarly journals POS0374 SENESCENCE DID NOT ALTER THE CHONDROPROTECTIVE EFFECT OF EXTRACELLULAR VESICLES FROM MESENCHYMAL STROMAL CELLS

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 417.2-418
Author(s):  
J. Boulestreau ◽  
M. Maumus ◽  
P. Rozier ◽  
C. Jorgensen ◽  
D. Noel
Keyword(s):  
Extracellular Vesicles ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Total Protein Content ◽  
Type Iii Collagen ◽  
Γh2ax Foci ◽  
Oa Chondrocytes ◽  
The Impact ◽  
Chondroprotective Effect

Background:Age is the most important risk factor in degenerative osteoarthritis (OA) and is associated with the accumulation of senescent cells that contribute to functional decline of joint. We previously demonstrated that extracellular vesicles (EVs) from mesenchymal stromal cells (MSCs) largely mediate the therapeutic effect of parental cells in OA.Objectives:Here, we assessed the impact of senescence on the characteristics of EVs from adipose tissue-derived MSCs (ASC-EVs) and their properties in an in vitro model of OAMethods:ASCs were induced to senescence using 25µM etoposide for 24 hours. Senescence was assessed by quantifying proliferation rate, SA-βGal activity, nuclear γH2AX foci number, phalloidin staining and expression of cyclin dependent kinase inhibitors (CDKI) (RT-qPCR). ASC-EVs were isolated by differential ultracentrifugation and characterized by size, concentration, total protein content, structure (cryo-TEM) and immunophenotype. In vitro OA model used chondrocytes isolated from OA patients, which were stimulated with IL1β for 48h before culture with ASCs or ASC-EVs for 7 days. Expression of chondrocytic and inflammatory markers was quantified by RT-qPCR and SASP factors were quantified by ELISA in supernatants.Results:Senescence-induced ASCs experienced growth arrest and increase of SA-βGal staining, of p21 CDKI expression, of nuclear γH2AX foci, of stress fibers and of several SASP factors (IL6, IL8, MMP3) confirming the expression of main senescence features. Senescent ASCs produced 4-fold more EVs than healthy ASCs and senescent ASC-EVs were larger. In vitro, both healthy and senescent ASCs decreased fibrotic markers (type III COLLAGEN), catabolic and hypertrophic markers (MMP3, MMP13, AP) and increased COX2 expression in OA chondrocytes. By contrast, healthy ASCs decreased the expression of IL6 while senescent ASCs highly increased IL6. Looking at the role of ASC-EVs on OA chondrocytes, we found out that both healthy and senescent ASC-EVs were able to increase the expression of AGG and type II COLLAGEN while they decreased the expression of MMP13, AP, type X COLLAGEN, HMOX1 and IL6. Finally, healthy and senescent ASC-EVs decreased the number of SA-βGal positive chondrocytes but did not impact the expression of p21 in IL1β-induced chondrocytes.Conclusion:Our results indicated a chondroprotective effect of ASC-EVs, independently of the senescent state of parental cells and suggested that EVs might act through different mechanisms than ASCs, which warrants further investigationDisclosure of Interests:Jérémy Boulestreau: None declared, Marie Maumus Employee of: Bauerfeind France, Pauline Rozier: None declared, Christian Jorgensen Shareholder of: Medxcell sciences, Consultant of: Medxcell sciences, Daniele Noel Shareholder of: Medxcell sciences, Consultant of: Medxcell sciences

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