Mesenchymal stromal cells

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Are mesenchymal stromal cells immune cells?

Are mesenchymal stromal cells immune cells?

Mesenchymal stromal cells (MSCs) are considered to be promising agents for the treatment of immunological disease. Although originally identified as precursor cells for mesenchymal lineages, in vitro studies have demonstrated that MSCs possess diverse immune regulatory capacities. Pre-clinical models have shown beneficial effects of MSCs in multiple immunological diseases and a number of phase 1/2 clinical trials carried out so far have reported signs of immune modulation after MSC infusion. These data indicate that MSCs play a central role in the immune response. This raises the academic question whether MSCs are immune cells or whether they are tissue precursor cells with immunoregulatory capacity. Correct understanding of the immunological properties and origin of MSCs will aid in the appropriate and safe use of the cells for clinical therapy. In this review the whole spectrum of immunological properties of MSCs is discussed with the aim of determining the position of MSCs in the immune system.
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Mesenchymal Stromal Cells in Transplantation Rejection and Tolerance

Mesenchymal Stromal Cells in Transplantation Rejection and Tolerance

2 Transplantation Research Immunology Group, Nuffield Department of Surgical Sciences, John Radcliffe Hospital, University of Oxford, Oxford 0X3 9DU, United Kingdom Correspondence: karen.english@nuim.ie Mesenchymal stromal cells (MSCs) have recently emerged as promising candidates for cell- based immunotherapy in solid organ transplantation (SOT). In addition to immune modu- lation, MSCs possess proreparative properties and preclinical studies indicate that MSCs have the capacity to prolong graft survival and in some cases induce tolerance. Currently, the application of MSCs in SOT is being evaluated in phase I/II clinical trials. Whereas the mechanisms of action used by MSC immunomodulation have been somewhat elucidated in vitro, the data from preclinical transplant models have been unclear. Furthermore, the optimal timing, dose, and route of administration remain to be elucidated. Importantly, MSCs have the ability to sense their environment, which may influence their function. In this article, we discuss the impact of the local microenvironment on MSCs and the mechanisms of MSC immunomodulation in the setting of SOT.
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Inflammatory regulation of glucocorticoid metabolism in mesenchymal stromal cells

Inflammatory regulation of glucocorticoid metabolism in mesenchymal stromal cells

The best-characterized of these mechanisms is the in- crease in 11␤-HSD1 expression in hepatocytes in re- sponse to GCs; this is mediated by members of the CCAAT/enhancer binding protein family and requires new protein synthesis (17). However, to date none of these studies have characterized signaling systems in- volved in mediating the effects of proinflammatory cytokines and GCs in mesenchymal stromal cells. This raises the possibility that novel regulatory pathways regulate these effects. Furthermore, the presence of distinct regulatory mechanisms in musculoskeletal cells might enable tissue-specific regulation of 11␤-HSD1 activity. In this study we examined the mechanisms underlying the regulation of 11␤-HSD1 expression and activity in osteoblasts, synovial fibroblasts, and myo- blasts.
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Effects of senolytic drugs on human mesenchymal stromal cells

Effects of senolytic drugs on human mesenchymal stromal cells

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. Keywords: Senolytic drugs, Senescence, Mesenchymal stromal cells, DNA methylation, Telomere attrition, ABT-263, Quercetin, Danazol, Nicotinamide riboside

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Multipotent mesenchymal stromal cells. original research report

Multipotent mesenchymal stromal cells. original research report

Hematol Oncol Stem Cell Ther 2013; 6(1): 1–8 ª 2013, King Faisal Specialist Hospital & Research Centre. Published by Elsevier Ltd. All rights reserved. DOI: http://dx.doi.org/10.1016/j.hemonc.2013.02.002 BACKGROUND AND OBJECTIVES: Umbilical cord blood is an important source of stem cells. However, isolating multipotent mesenchymal stromal cells (MSCs) from umbilical cord blood presents methodological challenges. We compared the effectiveness of six approaches to improve the success rate of MSC isolation and proliferation from umbilical cord blood.

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Bone marrow-derived mesenchymal stromal cells differ in their attachment to fibronectin-derived peptides from term placenta-derived mesenchymal stromal cells

Bone marrow-derived mesenchymal stromal cells differ in their attachment to fibronectin-derived peptides from term placenta-derived mesenchymal stromal cells

Jan K. Maerz 1 , Lorenzo P. Roncoroni 1 , David Goldeck 2 , Tanja Abruzzese 1 , Hubert Kalbacher 3 , Bernd Rolauffs 4 , Peter DeZwart 4 , Kay Nieselt 5 , Melanie L. Hart 1 , Gerd Klein 2 and Wilhelm K. Aicher 1* Abstract Introduction: Human mesenchymal stromal cells (MSCs) can be isolated from different sources including bone marrow and term placenta. These two populations display distinct patterns of proliferation and differentiation in vitro. Since proliferation and differentiation of cells are modulated by cell – matrix interactions, we investigated the attachment of MSCs to a set of peptide-coated surfaces and explored their interactions with peptides in
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From human mesenchymal stromal cells to osteosarcoma cells classification by deep learning

From human mesenchymal stromal cells to osteosarcoma cells classification by deep learning

The ability of DL to detect critical features from complex datasets is a significant achievement in early diagnosis and cell cancer progression. In this paper, we focus the attention on osteosarcoma. Osteosarcoma is one of the primary malignant bone tumors which usually afflicts people in adolescence. Our contribution to classification of osteosarcoma cells is made as follows: a DL approach is applied to discriminate human Mesenchymal Stromal Cells (MSCs) from osteosarcoma cells and to classify the different cell populations under investigation. Glass slides of different cell populations were cultured including MSCs, differentiated in healthy bone cells (osteoblasts) and osteosarcoma cells, both single cell populations or mixed. Images of such samples of isolated cells (single-type of mixed) are recorded with traditional optical microscopy. DL is then applied to identify and classify single cells. Proper data augmentation techniques and cross-fold validation are used to appreciate the capabilities of a convolutional neural network to address the cell detection and classification problem. Based on the results obtained on individual cells, and to the versatility and scalability of our DL approach, the next step will be its application to discriminate and classify healthy or cancer tissues to advance digital pathology.
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The Response of Vocal Fold Fibroblasts and Mesenchymal Stromal Cells to Vibration

The Response of Vocal Fold Fibroblasts and Mesenchymal Stromal Cells to Vibration

In the development of a biomimetic tissue engineering construct for the vocal fold lamina propria, use of hVFF has apparent advantages given they are the native cell; however, healthy hVFF are unavailable commercially and primary cells are very difficult to acquire for transplantation. It is therefore necessary to investigate the suitability of other cell types for transplantation as measured by their response to mechanical forces that are common to the vocal fold lamina propria. Mesenchymal stromal cells originally isolated from bone marrow (BM-MSC), possess the ability to differentiate along multiple tissue lineages, participate in tissue repair and regeneration through a variety of paracrine mechanisms and suppress activation and proliferation of immune and inflammatory cells [13]. Hanson et al. have determined that hVFF indeed exhibit functionally similar characteristics to BM-MSC as defined by cell surface markers, differentiation potential, and immuno- phenotype [14]. The similar characteristics of these two cell types may designate BM-MSC as a viable cell for vocal fold tissue engineering. In addition to functional similarity, the benefits of using BM-MSC include their capacity for significant cell
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The expression of marker genes during the differentiation of mesenchymal stromal cells

The expression of marker genes during the differentiation of mesenchymal stromal cells

Mesenchymal stromal cells (MSCs) are an excellent and easily accessible source of precursor cells that have applications in regenerative medicine. They can be obtained from almost any tissue; however, bone marrow, Wharton’s jelly and adipose tissue are the most frequently used sources of MSCs. Increased interest in using MSCs in medical procedures has resulted in a pressing need to identify the genetic elements that can indicate the presence and the characteristics of MSCs. Genomic profiling enables the identification and characteriza- tion of MSCs as well as finding biomarkers and key molecules involved in all processes occurring in the cell. This knowledge is essential for developing a stem cell approach for tissue engineering and can improve the development of new clinical applications of MSCs. This review is an attempt to give an overview of key genetic markers indicating the main directions of MSC differentiation. The expression of these genes provides information about the direction and progress of differentiation and about interactions with the surrounding environment as well as specific molecular pathways that MSCs are involved in.
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Effects of Normothermic Machine Perfusion Conditions on Mesenchymal Stromal Cells

Effects of Normothermic Machine Perfusion Conditions on Mesenchymal Stromal Cells

Ex-situ normothermic machine perfusion (NMP) of transplant kidneys allows assessment of kidney quality and targeted intervention to initiate repair processes prior to transplantation. Mesenchymal stromal cells (MSC) have been shown to possess the capacity to stimulate kidney repair. Therefore, the combination of NMP and MSC therapy offers potential to repair transplant kidneys. It is however unknown how NMP conditions affect MSC. In this study the effect of NMP perfusion fluid on survival, metabolism and function of thawed cryopreserved human (h)MSC and porcine (p)MSC in suspension conditions was studied. Suspension conditions reduced the viability of pMSC by 40% in both perfusion fluid and culture medium. Viability of hMSC was reduced by suspension conditions by 15% in perfusion fluid, whilst no differences were found in survival in culture medium. Under adherent conditions, survival of the cells was not affected by perfusion fluid. The perfusion fluid did not affect survival of fresh MSC in suspension compared to the control culture medium. The freeze-thawing process impaired the survival of hMSC; 95% survival of fresh hMSC compared to 70% survival of thawed hMSC. Moreover, thawed MSC showed increased levels of reactive oxygen species, which indicates elevated levels of oxidative stress, and reduced mitochondrial activity, which implies reduced metabolism. The adherence of pMSC and hMSC to endothelial cells was reduced after the thawing process, effect which was particularly profound in in the perfusion fluid. To summarize, we observed that conditions required for machine perfusion are influencing the behavior of MSC. The freeze-thawing process reduces survival and metabolism and increases oxidative stress, and diminishes their ability to adhere to endothelial cells. In addition, we found that hMSC and pMSC behaved differently, which has to be taken into consideration when translating results from animal experiments to clinical studies.
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Supernatant of Bone Marrow Mesenchymal Stromal Cells Induces Peripheral Blood Mononuclear Cells Possessing Mesenchymal Features

Supernatant of Bone Marrow Mesenchymal Stromal Cells Induces Peripheral Blood Mononuclear Cells Possessing Mesenchymal Features

Increasing evidence shows that some cells from peripheral blood fibroblast-like mononuclear cells have the capacity to differentiate into mesenchymal lineages. However, the insufficiency of these cells in the circulation challenges the cell isolation and subsequently limits the clinical application of these cells. In the present study, the peripheral blood mononuclear cells (pbMNCs) were isolated from wound animals and treated with the supernatant of bone marrow mesenchymal stromal cells (bmMSCs). Results showed these pbMNCs were fibro- blast-like, had stromal morphology, were negative for CD34 and CD45, but positive for Vimentin and Collagen I, and had the multipotency to differentiate into adipocytes and os- teoblasts. We named these induced peripheral blood-derived mesenchymal stromal cells (ipbMSCs). Skin grafts in combination with ipbMSCs and collagen I were applied for wound healing, and results revealed ipbMSC exhibited similar potency and effectiveness in the promotion of wound healing to the bmMSCs. Hereafter, we speculate that the mixture of growth factors and chemokines secreted by bmMSCs may play an important roles in the induction of the proliferation and mesenchymal differentiation of mononuclear cells. Our results are clinically relevant because it provide a new method for the acquisition of MSCs which can be used as a candidate for the wound repair.
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Reparative effect of mesenchymal stromal cells on endothelial cells after hypoxic and inflammatory injury

Reparative effect of mesenchymal stromal cells on endothelial cells after hypoxic and inflammatory injury

Jesus M. Sierra-Parraga 1* , Ana Merino 1 , Marco Eijken 2,3 , Henri Leuvenink 4 , Rutger Ploeg 5 , Bjarne K. Møller 3 , Bente Jespersen 2,6 , Carla C. Baan 1 and Martin J. Hoogduijn 1 Abstract Background: The renal endothelium is a prime target for ischemia-reperfusion injury (IRI) during donation and transplantation procedures. Mesenchymal stromal cells (MSC) have been shown to ameliorate kidney function after IRI. However, whether this involves repair of the endothelium is not clear. Therefore, our objective is to study potential regenerative effects of MSC on injured endothelial cells and to identify the molecular mechanisms involved.
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Phenotype instability of hepatocyte-like cells produced by direct reprogramming of mesenchymal stromal cells

Phenotype instability of hepatocyte-like cells produced by direct reprogramming of mesenchymal stromal cells

Methods: iHEPs were generated by forced expression of Foxa2/Hnf4a in mouse mesenchymal stromal cells and characterized their phenotype stability by in vitro and in vivo analyses. Results: The iHEPs expressed mixed hepatocyte and liver progenitor cell markers, were highly proliferative, and presented metabolic activities in functional assays. A progressive loss of hepatic phenotype, however, was observed after several passages, leading to an increase in alpha-SMA + fibroblast-like cells, which could be distinguished and sorted from iHEPs by differential mitochondrial content. The resulting purified iHEPs proliferated, maintained liver progenitor cell markers, and, upon stimulation with lineage maturation media, increased expression of either biliary or hepatocyte markers. In vivo functionality was assessed in independent pre-clinical mouse models. Minimal engraftment was observed following transplantation in mice with acute acetaminophen-induced liver injury. In contrast, upon transplantation in a transgenic mouse model presenting host hepatocyte senescence, widespread engraftment and uncontrolled proliferation of iHEPs was observed, forming islands of epithelial-like cells, adipocyte- like cells, or cells presenting both morphologies.
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Differentiation of Equine Mesenchymal Stromal Cells into Cells of Neural Lineage: Potential for Clinical Applications

Differentiation of Equine Mesenchymal Stromal Cells into Cells of Neural Lineage: Potential for Clinical Applications

Mesenchymal stromal cells (MSCs) are able to differentiate into extramesodermal lineages, including neurons. Positive outcomes were obtained after transplantation of neurally induced MSCs in laboratory animals after nerve injury, but this is unknown in horses. Our objectives were to test the ability of equine MSCs to differentiate into cells of neural lineage in vitro, to assess differences in morphology and lineage-specific protein expression, and to investigate if horse age and cell passage number affected the ability to achieve differentiation. Bone marrow-derived MSCs were obtained from young and adult horses. Following demonstration of stemness, MSCs were neurally induced and microscopically assessed at different time points. Results showed that commercially available nitrogen-coated tissue culture plates supported proliferation and differentiation. Morphological changes were immediate and all the cells displayed a neural crest-like cell phenotype. Expression of neural progenitor proteins, was assessed via western blot or immunofluorescence. In our study, MSCs generated from young and middle-aged horses did not show differences in their ability to undergo differentiation. The effect of cell passage number, however, is inconsistent and further experiments are needed.
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Inhibition of mesenchymal stromal cells by pre-activated lymphocytes and their culture media

Inhibition of mesenchymal stromal cells by pre-activated lymphocytes and their culture media

mesenchymal stem cells added to corticosteroid therapy for the treatment of acute graft-versus-host disease. Biol Blood Marrow Transplant 2009, 15:804 – 811. 11. Lucchini G, Introna M, Dander E, Rovelli A, Balduzzi A, Bonanomi S, Salvadè A, Capelli C, Belotti D, Gaipa G, Perseghin P, Vinci P, Lanino E, Chiusolo P, Orofino MG, Marktel S, Golay J, Rambaldi A, Biondi A, D ’ Amico G, Biagi E: Platelet-lysate-expanded mesenchymal stromal cells as a salvage therapy for severe resistant graft-versus-host disease in a pediatric population. Biol Blood Marrow Transplant 2010, 16:1293 – 1301.
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The osteogenic response of mesenchymal stromal cells to strontium-substituted bioactive glasses

The osteogenic response of mesenchymal stromal cells to strontium-substituted bioactive glasses

To summarize, a small but growing body of work suggests that strontium-substituted bioactive glasses may form the basis for the development of improved bone graft substitutes. Therefore, the aim of this study was to investigate the effect of particulate strontium- substituted bioactive glasses on the metabolic activity and osteogenic differentiation of mesenchymal stromal cells isolated from rat bone marrow, in order to evaluate their potential use in composite materials for bone regen- eration applications. Bioactive glasses based on the 45S5 composition were fabricated in which calcium oxide was substituted by strontium oxide on a molar basis. These were characterized using a range of techniques in order to determine how the substitution affected various physi- cal properties. Finally, the in vitro effect of the bioactive glasses on the metabolic activity and osteogenic potential of mesenchymal stromal cells was investigated in order to provide a better understanding of their regenerative capacity.
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The osteogenic response of mesenchymal stromal cells to strontium-substituted bioactive glasses.

The osteogenic response of mesenchymal stromal cells to strontium-substituted bioactive glasses.

To summarize, a small but growing body of work suggests that strontium-substituted bioactive glasses may form the basis for the development of improved bone graft substitutes. Therefore, the aim of this study was to investigate the effect of particulate strontium- substituted bioactive glasses on the metabolic activity and osteogenic differentiation of mesenchymal stromal cells isolated from rat bone marrow, in order to evaluate their potential use in composite materials for bone regen- eration applications. Bioactive glasses based on the 45S5 composition were fabricated in which calcium oxide was substituted by strontium oxide on a molar basis. These were characterized using a range of techniques in order to determine how the substitution affected various physi- cal properties. Finally, the in vitro effect of the bioactive glasses on the metabolic activity and osteogenic potential of mesenchymal stromal cells was investigated in order to provide a better understanding of their regenerative capacity.
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Magnetic targeting as a strategy to enhance therapeutic effects of mesenchymal stromal cells

Magnetic targeting as a strategy to enhance therapeutic effects of mesenchymal stromal cells

Luisa H. A. Silva 1 , Fernanda F. Cruz 1 , Marcelo M. Morales 2 , Daniel J. Weiss 3 and Patricia R. M. Rocco 1* Abstract Mesenchymal stromal cells (MSCs) have been extensively investigated in the field of regenerative medicine. It is known that the success of MSC-based therapies depends primarily on effective cell delivery to the target site where they will secrete vesicles and soluble factors with immunomodulatory and potentially reparative properties.

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Strategies to improve the therapeutic effects of mesenchymal stromal cells in respiratory diseases

Strategies to improve the therapeutic effects of mesenchymal stromal cells in respiratory diseases

Luisa H. A. Silva 1 , Mariana A. Antunes 1,2 , Claudia C. Dos Santos 3 , Daniel J. Weiss 4 , Fernanda F. Cruz 1,2 † and Patricia R. M. Rocco 1,2* † Abstract Due to their anti-inflammatory, antiapoptotic, antimicrobial, and antifibrotic properties, mesenchymal stromal cells (MSCs) have been considered a promising alternative for treatment of respiratory diseases. Nevertheless, even though MSC administration has been demonstrated to be safe in clinical trials, to date, few studies have shown evidence of MSC efficacy in respiratory diseases. The present review describes strategies to enhance the beneficial effects of MSCs, including preconditioning (under hypoxia, oxidative stress, heat shock, serum deprivation, and exposure to inflammatory biological samples) and genetic manipulation. These strategies can variably promote increases in MSC survival rates, by inducing expression of cytoprotective genes, as well as increase MSC potency by improving secretion of reparative factors. Furthermore, these strategies have been demonstrated to enhance the beneficial effects of MSCs in preclinical lung disease models. However, there is still a long way to go before such strategies can be translated from bench to bedside.
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Response of human chondrocytes and mesenchymal stromal cells to a decellularized human dermis

Response of human chondrocytes and mesenchymal stromal cells to a decellularized human dermis

Yang Q et al. and Yang Z et al. developed a natural acellular 3D interconnected porous scaffold which resulted in a valid support for the attachment, proliferation and dif- ferentiation of bone marrow mesenchymal stromal cells into chondrocytes. Gong et al. proposed a sandwich model of an acellular cartilage sheet for in vitro and in vivo cartilage engineering, thus mimicking the native environment and the structure of cartilage. Finally, a previous study by the current authors on the behaviour of a decellularized human dermis (HDM_derm), cul- tured with primary rat tenocytes, showed in vitro a high biological performance and mechanical competence of HDM_derm [14].
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