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The influence of equine bone marrow derived stem cells on the response of cultured peripheral blood mononuclear cells to endotoxinMacDonald, Elizabeth Steward 05 October 2015 (has links)
Endotoxemia is a major cause of morbidity and mortality in horses. The presence of large amounts of circulating endotoxin inititates a number of cell signaling pathways leading to a systemic inflammatory response. Activation of these pathways causes the release of a number of pro- and anti-inflammatory mediators. An overwhelming release of these mediators leads to the development of clinical signs associated with endotoxemia. Treatment options are limited mostly to supportive care at this time. Mesenchymal stem cells (MSCs) have been shown to have anti-inflamamtory and immune modulatory effects that may have some benefit for the treatment of horses with endotoxemia.
To evaluate the effect of equine MSCs on the response to endotoxin challenge, the study was performed on two different stem cell lines with peripheral blood mononuclear cells (PBMCs) used as controls. After stimulation with endotoxin, secretion of tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), interleukin-10 (IL-10), and interferon gamma (IFN-γ) were determined by ELISA. The immunogenic properties of MSCs were assessed with a one-way mixed lymphocyte reaction. In addition, the ability of MSCs to alter production of cytokines from stimulated PBMCs was assessed.
TNF-α was not produced by MSCs when compared to PBMCs (p = < 0.001). There was no significant difference between MSCs and PBMCs in the production of IL-6. IL-10 production was significantly different (p = <0.001) at 6 and 12 hours with MSCs producing more than PBMCs in one stem cell line only. MSCs did not stimulate proliferation of PBMCs. Co-incubation of MSCs with PBMCs decreased the production of TNF-α in both stem cell lines although it was not statistically significant (p = 0.4 and 0.9) at either time point. IL-6 secretion was suppressed at twelve hours with co-incubation. IL-10 production was increased with co-incubation in one stem cell line. MSCs secrete soluble factors that can alter PBMC cytokine production and they do not appear to be immunostimulatory. These findings have potential implication for treatment of equine inflammatory conditions. / Master of Science
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Mesenchymal Stem Cell Mechanobiology and Tendon RegenerationYoungstrom, Daniel W. 10 April 2015 (has links)
Tendon function is essential for quality of life, yet the pathogenesis and healing of tendinopathy remains poorly understood compared to other musculoskeletal disorders. The aim of regenerative medicine is to replace traditional tissue and organ transplantation by harnessing the developmental potential of stem cells to restore structure and function to damaged tissues. The recently discovered interdependency of cell phenotype and biophysical environment has created a paradigm shift in cell biology. This dissertation introduces a dynamic in vitro model for tendon function, dysfunction and development, engineered to characterize the mechanobiological relationships dictating stem cell fate decisions so that they may be therapeutically exploited for tendon healing.
Cells respond to mechanical deformation via a complex set of behaviors involving force-sensitive membrane receptor activity, changes in cytoskeletal contractility and transcriptional regulation. Effective ex vivo model systems are needed to emulate the native environment of a tissue and to translate cell-matrix forces with high fidelity. A naturally-derived decellularized tendon scaffold (DTS) was invented to serve as a biomimetic tissue culture platform, preserving the structure and function of native extracellular matrix. DTS in concert with a newly designed dynamic mechanical strain system comprises a tendon bioreactor that is able to emulate the three-dimensional topography, extracellular matrix proteins, and mechanical strain that cells would experience in vivo. Mesenchymal stem cells seeded on decellularized tendon scaffolds subject to cyclic mechanical deformation developed strain-dependent alterations in phenotype and measurably improved tissue mechanical properties. The relative tenogenic efficacies of adult stem cells derived from bone marrow, adipose and tendon were then compared in this system, revealing characteristics suggesting tendon-derived mesenchymal stem cells are predisposed to differentiate toward tendon better than other cell sources in this model.
The results of the described experiments have demonstrated that adult mesenchymal stem cells are responsive to mechanical stimulation and, while exhibiting heterogeneity based on donor tissue, are broadly capable of tenocytic differentiation and tissue neogenesis in response to specific ultrastructural and biomechanical cues. This knowledge of cellular mechanotransduction has direct clinical implications for how we treat, rehabilitate and engineer tendon after injury. / Ph. D.
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The immunomodulatory properties of messenchymal stem cells and their use for immunotherapy.Hoogduijn, Martin J., Popp, F., Verbeek, R., Masoodi, Mojgan, Nicolaou, Anna, Baan, C., Dehlke, M-H. January 2010 (has links)
No / There is growing interest in the use of mesenchymal stem cells (MSC) for immune therapy. Clinical trials that use MSC for treatment of therapy resistant graft versus host disease, Crohn's disease and organ transplantation have initiated. Nevertheless, the immunomodulatory effects of MSC are only partly understood. Clinical trials that are supported by basic research will lead to better understanding of the potential of MSC for immunomodulatory applications and to optimization of such therapies. In this manuscript we review some recent literature on the mechanisms of immunomodulation by MSC in vitro and animal models, present new data on the secretion of pro-inflammatory and anti-inflammatory cytokines, chemokines and prostaglandins by MSC under resting and inflammatory conditions and discuss the hopes and expectations of MSC-based immune therapy.
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Characterisation of human fetal mesenchymal stem cells /Götherström, Cecilia, January 2004 (has links)
Diss. (sammanfattning) Stockholm : Karol. inst., 2004. / Härtill 5 uppsatser.
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Analysis of in vitro functions of mesenchymal stem cells isolated from different human tissues / Skirtingų suaugusio žmogaus audinių mezenchiminių kamieninių ląstelių funkcionavimo mechanizmų tyrimaiTunaitis, Virginijus 07 March 2011 (has links)
Human mesenchymal stem cells (MSC) have attracted a great deal of interest for their potential use in regenerative medicine and suppression of the inflammation. Nevertheless, all known therapy protocols require large amounts of MSCs, which can be obtained only by in vitro expansion. One of the most important methodological problems is associated with the use of animal-derived components in the cell culture medium. The main aim of the current research was to elucidate the influence of different serum substitutes on the proliferation, differentiation, expression of cell surface markers, and total protein expression of mesenchymal stem cells derived from human adipose tissue. In addition we were aiming to determine the features of mesenchymal stem cell populations from an exfoliated deciduous tooth (SHED) and their response to the multifunctional proinflammatory protein alpha1-antitrypsin. Our results indicate that adipose tissue derived MSCs cultivated in the presence of fetal calf serum and allogeneic human serum display similar properties, while synthetic serum substitute induces increase in growth and differentiation potential of MSCs. Moreover, our results indicate, that synthetic serum substitute also activates transcription of genes related to adipogenic and osteogenic differentiation and diminishes expression of cell surface marker CD146. In the present study, we used a proteomic approach that allowed us to compare protein expression signatures between primary cell... [to full text] / Žmogaus suaugusio organizmo mezenchiminės kamieninės ląstelės (MKL) pradėtos sėkmingai naudoti pažeistų audinių regeneracijai ir uždegiminio proceso slopinimui. Šiuolaikiniams terapijos protokolams yra reikalingi dideli ląstelių kiekiai, todėl prieš naudojimą yra būtina jas padauginti in vitro. Tačiau naudojant skirtingus MKL išskyrimo, in vitro kultivavimo ir padauginimo protokolus, yra sunku lyginti mokslinių tyrimų duomenis ir klinikinių tyrimų rezultatus. Nevienodos kultivavimo sąlygos gali įtakoti MKL funkcines savybes (augimo greitį, gebėjimą diferencijuotis, migracinį aktyvumą ir kt.). Šiame disertaciniame darbe tyrėme auginimo terpių, praturtintų skirtingais serumais (gyvulinės kilmės serumai, žmogaus alogeninis serumas, sintetinis serumas), poveikį žmogaus riebalinio audinio MKL. Taip pat charakterizavome MKL išskirtas iš žmogaus pieninių dantų pulpos ir palyginome šių ląstelių kultūros bei jų dukterinių klonų savybės. Kompleksiškai tyrėme uždegimo antiproteinazės alfa1-antitripsino (AAT) poveikį šioms ląstelėms. Nustatėme, kad, lyginant su kitais tyrime naudotais serumais, sintetinis serumo pakaitalas geriausiai skatino MKL augimą bei gebėjimą diferencijuotis adipogenine ir osteogenine kryptimis. Taip pat, skirtingai nuo kitų naudotų gyvulinės kilmės ir žmogaus serumų, sintetinis serumo pakaitalas veikė kaip adipogeninės ir osteogeninės diferenciacijos indukcijai svarbių genų PPARγ ir Msx2 transkripcijos aktyvatorius. Be to, sintetinis serumo pakaitalas slopino... [toliau žr. visą tekstą]
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Translational Predictive Model for Heart Failure Recovery in LVAD Patients Receiving Stem Cell TherapyMikail, Philemon January 2016 (has links)
Introduction: Heart failure remains a major public health problem, with recent estimates indicating that end-stage heart failure with two-year mortality rates of 70-80% affects over 60,000 patients in the US each year. Medical management can be used but success declines for patients with end stage heart failure. Although cardiac transplantation is optimal, less than 2500 cardiac transplants are performed annually due to the severely limited supply of donor organs. Mechanical circulatory support (MCS) devices are now routinely used to bridge patients with end-stage heart failure who become critically ill until a donor heart is available. The use of stem cell therapy to treat heart failure has been gaining significant ground in recent years, specifically due to its regenerative properties, and both animal and human models have shown significant improvements in ventricular mass, ejection fraction, vascularization, wall thickness, and infarct size reduction. Using the patients' HeartWare HVAD device diagnostics, we were able to acquire our response variable; pulsatility. Pulsatility is a variable measure of the differential between minimum and maximum flow and is dependent on device motor speed, power, current, and fluid viscosity. This measurement is important as it relates to the contractility of the heart and could potentially be used as an end point in determining when a patient is healthy enough to have their HVAD explanted. We set out to develop a low cost and effective predictive model to determine amniotic mesenchymal stem cell's ability to repair compromised cardiac tissue of patients using the Total Artificial Heart (TAH) and Donovan Mock Circulation Tank (DMC). Methods: Predictive modelling was performed using the TAH and DMC. The system was set to a range from critical heart failure to a normal operating conditions through the variation of preload, afterload, and ventricular drive pressures with the intent of comparing the results to our patient population. Patients (n=7, 3 dilated, 4 ischemic) received intravenous and intra-myocardial injections of a heterogeneous amniotic mesenchymal stem cells mixture and liquid matrix (MSCs+LM) at HVAD implant. Groups were analyzed based on treatment; control (HVAD only, n=7) versus stem cells (HVAD + MSCs+LM). HeartWare log files were acquired from patients' devices and analyzed in SAS and Matlab. Results from the patient study were compared to the predictive model to determine levels of stem cell response. Results: Pulsatility was found to increase with left drive pressure and afterload. Lower drive pressures resulted in a drop off in pulsatility at higher afterloads while higher drive pressures were able to compensate for any afterload. Pulsatility also increased with preload but lower drive pressures were unable to fully eject at the highest preloads, resulting in a reduced pulsatility. We observed the effects of the stem cell injections on pulsatility and found that patients receiving therapy demonstrated statistically significant increases in pulsatility at 15-20 (p=.0487), 25-30 (p=.0131), 35-40 (p=.0333), and 75-80 (p=0.0476) days post implant. At minimum, when comparing the patient results to the in vitro model, the therapy resulted in a progression from end stage HF conditions to medium cardiac function conditions. At maximum, the therapy resulted in a progression from end stage HF to normal healthy operating cardiac function. Conclusions: Stem cells demonstrated a significantly increased rate of change in pulsatility within the first 40 days and at 80 days post implant when compared to control. They also demonstrated progression from end stage HF to normal healthy cardiac function at two time periods (Days 40, 90). These results justify expansion of the study to encompass a larger patient population to verify the results of the in vitro model to predict cardiac regeneration with multiple functional status indicators.
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Transplantation of mesenchymal stem cells and injections of microRNA as therapeutics for nervous system repairKolar, Mallappa K. January 2016 (has links)
Traumatic injuries to the spinal cord (SCI) and peripheral nerve (PNI) affect several thousand people worldwide every year. At present, there is no effective treatment for SCI and despite continuous improvements in microsurgical reconstructive techniques for PNI, many patients are still left with permanent, devastating neurological dysfunction. This thesis investigates the effects of mesenchymal stem cells (MSC) derived from adipose (ASC) and dental (DSC) tissue and chitosan/microRNA-124 polyplex particles on regeneration after spinal cord and peripheral nerve injury in adult rats. Dental stem cells were obtained from apical papilla, dental pulp, and periodontal ligament. ASC and DSC expressed MSC surface markers (CD73, CD90, CD105 and CD146) and various neurotrophic molecules including BDNF, GDNF, NGF, VEGF-A and angiopoietin-1. Growth factor stimulation of the stem cells resulted in increased secretion of these proteins. Both ASC and DSC supported in vitro neurite outgrowth and in contrast to Schwann cells, ASC did not induce activation of astrocytes. Stimulated ASC also showed an enhanced ability to induce capillary-like tube formation in an in vitro angiogenesis assay. In a peripheral nerve injury model, ASC and DSC were seeded into a fibrin conduit, which was used to bridge a 10 mm rat sciatic nerve gap. After 2 weeks, both ASC and DSC promoted axonal regeneration in the conduit and reduced caspase-3 expression in the dorsal root ganglion (DRG). ASC also enhanced GAP-43 and ATF-3 expression in the spinal cord, reduced c-jun expression in the DRG and increased the vascularity of the implant. After transplantation into injured C3-C4 cervical spinal cord, ASC continued to express neurotrophic factors and laminin and stimulated extensive ingrowth of 5HT-positive raphaespinal axons into the trauma zone. In addition, ASC induced sprouting of raphaespinal terminals in C2 contralateral ventral horn and C6 ventral horn on both sides. Transplanted cells also changed the structure and the density of the astroglial scar. Although the transplanted cells had no effect on the density of capillaries around the lesion site, the reactivity of OX42-positive microglial cells was markedly reduced. However, ASC did not enhance recovery of forelimb function. In order to reduce activation of microglia/macrophages and the secondary tissue damage after SCI, the role of microRNA-124 was investigated. In vitro transfection of chitosan/microRNA-124 polyplex particles into rat microglia resulted in the reduction of reactive oxygen species and TNF-α levels and lowered expression of MHC-II. Upon microinjection into uninjured rat spinal cords, particles formed with Cy3-labeled control sequence RNA, were specifically internalized by OX42 positive macrophages and microglia. Alternatively, particles injected in the peritoneum were transported by macrophages to the site of spinal cord injury. Microinjections of chitosan/microRNA-124 particles significantly reduced the number of ED-1 positive macrophages after SCI. In summary, these results show that human MSC produce functional neurotrophic and angiogenic factors, creating a more desirable microenvironment for neural regeneration after spinal cord and peripheral nerve injury. The data also suggests that chitosan/microRNA-124 particles could be potential treatment technique to reduce neuroinflammation.
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Skeletal muscle repair following Plantar nerve relocation on an extracellular matrix seeded with mesenchymal stem cells in PEGylated fibrin gel as a treatment model for volumetric muscle loss.Da Costa, Adriana Jocelyn 30 September 2014 (has links)
The toll skeletal muscle injury, resulting in significant muscle mass loss, has on the patient reaches far more than physical and emotional, as the tolls are financial as well. Approximately more than 3 billion dollars is spent on the initial medical costs and on subsequent disability benefits, following a volumetric muscle loss. Skeletal muscle has a robust capacity for self-repair; this propensity for repair is hindered when skeletal muscle loss is larger than 20% of the total mass of the muscle. Previous work in our lab, has shown functional and morphological improvements following the cellular therapy, with mesenchymal stem cells (MSC), as well as with nerve relocation to the extracellular matrix (ECM). To further observe the regenerative properties of the above treatments, a defect weighing approximately 307 ± 3.7 mg wet weight and measuring approximately 1x 1cm² was removed from the lateral gastrocnemius (LGAS) of male Sprague Dawley rats. Additionally, the medial branch of the plantar nerve was then relocated and implanted to the middle of the ECM. Seven days post injury bone-marrow derived mesenchymal stem cells were injected directly into the implant using a PEGylated Fibrin hydrogel (PEG). Following 56 days of recovery, partial functional restoration was observed in the LGAS ECM seeded with MSC and implanted with the plantar nerve. The LGAS produced 86.3 ± 5.8% of the contralateral LGAS, a value that was significantly higher than ECM implantation alone (p <.05). The implanted ECM seeded with MSC and implanted with the plantar nerve showed significant increases in blood vessel density and myofiber content (p <.05). The data suggest that a volumetric injury can be repaired by neurotization of an implanted muscle-derived ECM seeded with MSCs. / text
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Associations cellules souches mésenchymateuses et céramiques pour l'ingénierie tissulaire osseuse : intérêt du milieu cellulaire et de l'environnement tridimensionnel sur la différenciation ostéoblastique / Associations of mesenchymal stem cells and ceramics for bone tissue engineeringCordonnier, Thomas 29 October 2010 (has links)
Les affections ostéo-articulaires concernent des millions de personnes. L’ingénierietissulaire osseuse, associant cellules souches mésenchymateuses humaines (CSM) etmatériaux synthétiques, pourrait répondre aux besoins cliniques. Pour cela, les différentescomposantes de cette approche et leur association doivent être mieux étudiées pour la rendreutile cliniquement. Durant cette thèse, une première étude animale proche du cas cliniquenous a permis de définir les points à améliorer pour le traitement des pertes osseuses. Nousavons ainsi pu développer un milieu spécifique induisant une différenciation rapide etterminale des CSM en ostéoblastes. Par la suite, l’utilisation de particules de céramiquescomme support cellulaire nous a permis d’obtenir des hybrides riches en matriceextracellulaire. Cet environnement 3D biomimétique permet l’engagement spontané des CSMvers un phénotype ostéoblastique et l’obtention d’une quantité osseuse importante in vivo.L’ensemble de ces résultats met en évidence l’importance de l’environnement et du stade dedifférenciation cellulaire pour la formation osseuse par ingénierie tissulaire osseuse. / Osteo-articular disorders affect millions of people over the world. Bone tissueengineering, an approach combining human mesenchymal stem cells (MSC) and syntheticmaterials, could potentially fulfill clinical needs. However, the different components of thisapproach and their association should be investigated further to make it clinically useful. Inthis thesis, an initial animal study close to clinical situation allowed us to identify areas thatneed improvement for regenerating bone defect. We were then able to develop a specificmedium which induces a rapid and terminal osteoblastic differentiation of MSC.Subsequently, the use of ceramic particles as cell support has allowed us to obtain hybridmainly composed of extracellular matrix. This biomimetic 3D environment allowsspontaneous osteoblastic commitment of MSC and induces a large bone quantity in vivo.Overall, these results highlight the importance of the environment and the cell differentiationstate for bone formation using bone tissue engineering.
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Vliv peptidů na osteogenní diferenciaci mesencyhmálních kmenových buněk / Effect of the peptides on osteogenic differentiation of mesenchymal steam cellsLukášová, Věra January 2015 (has links)
Osteogenic differentiation of mesenchymal stem cells (MSCs) would be possible to induce by creating of a cell bioactive scaffold that mimic the properties of bone extracellular matrix (ECM). This induction will be not only due to the addition of osteogenic supplements, but also due to the addition of differentiation peptides. These peptides activate signaling pathways leading to cell differentiation. The aim of this study was to evaluate the effect of selected peptides on adhesion, metabolic activity, proliferation and osteogenic differentiation of porcine MSCs. Four peptides with amino acid sequences of DGEA, IAGVGGEKSGGF, GQGFSYPYKAVFSTQ and KIPKASSVPTELSAISTLYL were selected. These peptides were derived from receptor binding sequences of collagen I, collagen III, BMP-7 and BMP-2 respectively. Scaffolds were prepared from a biocompatible and biodegradable poly-ε-caprolactone (PCL) polymer, suitable for cell cultivation. Cells were cultured on scaffolds for three weeks. Various concentration of differentiation peptides were added to the culture medium. As observed in the experiment of cells cultured in basal medium supplemented with differentiation peptides no effect on adhesion, proliferation or metabolic activity of porcine MSCs was observed. In groups treated with peptides derived from BMP-2...
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