| 1. |
- Duprez, Ida Rasmusson, et al.
(författare)
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Preparatory studies of composite mesenchymal stem cell islets for application in intraportal islet transplantation
- 2011
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Ingår i: Upsala Journal of Medical Sciences. - : Uppsala Medical Society. - 0300-9734 .- 2000-1967. ; 116:1, s. 8-17
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Tidskriftsartikel (refereegranskat)abstract
- Abstract Background. Low engraftment and adverse immune reactions hamper the success rate of clinical islet transplantation. In this study, we investigated the capacity of human mesenchymal stem cells (MSCs) to adhere to human islets of Langerhans and their effects in immune modulation and during blood interactions in vitro. Methods. Composite MSC-islets were formed by suspension co-culture, and the phenotype was evaluated by confocal microscopy. Islet function was assessed by dynamic insulin release in response to glucose in vitro. Mixed lymphocyte-islet reactions (MLIR) and the tubing blood loop model were utilized as in vitro tools to analyse the effect of MSCs on the innate and adaptive immune reactions triggered by the islets. Results. MSCs rapidly adhered to islets and spread out to cover the islet surface. Insulin expression and secretion were sustained with the MSC coating. MSC-coated islets showed unaffected reactions with blood in vitro in comparison to control islets. Furthermore, MSCs suppressed lymphocyte proliferation induced by islet cells in MLIR. Conclusion. We conclude that it is possible to create composite MSC-islets to enable delivery of the MSCs by utilizing the adhesive capacity of the MSCs. This could have beneficial immunosuppressive effects in optimizing pancreatic islet transplantation.
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| 2. |
- Fransson, Moa, et al.
(författare)
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Intranasal Delivery of CNS-Retargeted Human Mesenchymal Stromal Cells Prolongs Treatment Efficacy of Experimental Autoimmune Encephalomyelitis
- 2014
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Ingår i: Immunology. - : Wiley. - 0019-2805 .- 1365-2567. ; 142:3, s. 431-441
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Tidskriftsartikel (refereegranskat)abstract
- Treatment with mesenchymal stromal cells (MSC) is currently of interest for a number of diseases including multiple sclerosis (MS). MSCs is well known to target inflamed tissues however, in a therapeutic scenery, systemic administration will lead to few cells reaching the brain. We hypothesized that MSCs may target the brain upon intranasal (i.n) administration and persist in CNS tissue if expressing a CNS-targeting receptor. To demonstrate proof of concept, MSCs were genetically engineered to express a myelin oligodendrocyte glycoprotein (MOG)-specific receptor. Engineered MSCs retained their immunosuppressive capacity, infiltrated into the brain upon i.n. cell administration, and were able to significantly reduce disease symptoms of experimental autoimmune encephalomyelitis (EAE). The mice treated with CNS-targeting MSCs were resistant to further EAE induction whereas non-targeted MSC did not give such persistent effects. Histological analysis revealed increased brain restoration in engineered MSC-treated mice. In conclusion, MSCs can be genetically engineered to target the brain and prolong therapeutic efficacy in an EAE model.
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| 3. |
- Fransson, Moa, et al.
(författare)
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Mesenchymal stromal cells supportendothelial cell interactions in anintramuscular islet transplantation model
- 2015
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Ingår i: Regenerative Medicine Research. - : Springer Science and Business Media LLC. - 2050-490X. ; 3
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Tidskriftsartikel (refereegranskat)abstract
- Background:Mesenchymal stromal cells (MSC) have been under investigation for a number of therapies andhave lately been in focus as immunosuppressive actors in the field of transplantation. Herein we haveextended our previously published in vitro model of MSC-islets in an experimental setting of islettransplantation to the abdominal muscle.Human islets coated with luciferase-GFP transduced human MSC were transplanted to the abdomen muscletissue of NOD-scid ILR2γnull mice and cellular interactions were investigated by confocal microscopy.Results:The MSC reduced fibrotic encapsulation and facilitated endothelial cell interactions. In particular, weshow a decreased fraction of αSMA expressing fibrotic tissue surrounding the graft in presence of MSC-isletscompared to islets solely distributed into the muscle tissue. Also, in the presence of MSC, human isletendothelial cells migrated from the center of the graft out into the surrounding tissue forming chimeric bloodvessels with recipient endothelial cells. Further, in the graft periphery, MSC were seen interacting with infiltratingmacrophages.Conclusions:Here, in our experimental in vivo model of composite human islets and luciferase-GFP-transducedhuman MSC, we enable the visualization of close interactions between the MSC and the surrounding tissue. In thismodel of transplantation the MSC contribute to reduced fibrosis and increased islet endothelial cell migration.Furthermore, the MSC interact with the recipient vasculature and infiltrating macrophages.
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| 4. |
- Götherström, Cecilia, et al.
(författare)
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Fetal and adult multipotent mesenchymal stromal cells are killed by different pathways
- 2011
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Ingår i: Cytotherapy. - : Elsevier BV. - 1465-3249 .- 1477-2566. ; 13:3, s. 269-278
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Tidskriftsartikel (refereegranskat)abstract
- Background aims. Multipotent mesenchymal stromal cells, also known as mesenchymal stem cells (MSC), can be isolated from adult and fetal tissues. Recently, there has been considerable interest in MSC because they have features favorable for transplantation, namely their multipotency and non-immunogenic properties. Methods. We analyzed how human MSC derived from first-trimester fetal liver and adult bone marrow interact with naive and activated innate natural killer (NK) cells. NK cell function was studied by measuring killing of MSC, as well as degranulation (CD107a) induced by MSC. To assess the importance of NK cell killing, expression of surface epitopes was analyzed by flow cytometry on MSC before and after stimulation with interferon (IFN)gamma gamma. Results. Fetal and adult MSC express several ligands to activating NK cell receptors as well as low levels of HLA class I, with large inter-individual variation. Naive peripheral blood NK cells did not lyse fetal or adult MSC, whereas interleukin (IL)2 activated allogeneic as well as autologous NK cells did. Pre-incubation of MSC with IFN-gamma gamma increased their levels of HLA class I, protecting them from NK cell recognition. Fetal and adult MSC were preferably killed via the tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and Fas ligand (FasL) pathways, respectively. Blocking NKG2D reduced NK cell degranulation in both fetal and adult MSC. Conclusions. Fetal and adult MSC differ in their interactions with NK cells. Both fetal and adult MSC are susceptible to lysis by activated NK cells, which may have implications for the use of MSC in cell therapy.
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| 5. |
- Moll, Guido, et al.
(författare)
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Are Therapeutic Human Mesenchymal Stromal Cells Compatible with Human Blood?
- 2012
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Ingår i: Stem Cells. - : Oxford University Press (OUP). - 1066-5099 .- 1549-4918. ; 30:7, s. 1565-1574
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Tidskriftsartikel (refereegranskat)abstract
- Multipotent mesenchymal stromal cells (MSCs) are tested in numerous clinical trials. Questions have been raised concerning fate and function of these therapeutic cells after systemic infusion. We therefore asked whether culture-expanded human MSCs elicit an innate immune attack, termed instant blood-mediated inflammatory reaction (IBMIR), which has previously been shown to compromise the survival and function of systemically infused islet cells and hepatocytes. We found that MSCs expressed hemostatic regulators similar to those produced by endothelial cells but displayed higher amounts of prothrombotic tissue/stromal factors on their surface, which triggered the IBMIR after blood exposure, as characterized by formation of blood activation markers. This process was dependent on the cell dose, the choice of MSC donor, and particularly the cell-passage number. Short-term expanded MSCs triggered only weak blood responses in vitro, whereas extended culture and coculture with activated lymphocytes increased their prothrombotic properties. After systemic infusion to patients, we found increased formation of blood activation markers, but no formation of hyperfibrinolysis marker D-dimer or acute-phase reactants with the currently applied dose of 1.0-3.0 x 10(6) cells per kilogram. Culture-expanded MSCs trigger the IBMIR in vitro and in vivo. Induction of IBMIR is dose-dependent and increases after prolonged ex vivo expansion. Currently applied doses of low-passage clinical-grade MSCs elicit only minor systemic effects, but higher cell doses and particularly higher passage cells should be handled with care. This deleterious reaction can compromise the survival, engraftment, and function of these therapeutic cells.
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| 6. |
- Moll, Guido, et al.
(författare)
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Mesenchymal Stromal Cells Engage Complement and Complement Receptor Bearing Innate Effector Cells to Modulate Immune Responses (Open Access)
- 2011
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 6:7, s. e21703-
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Tidskriftsartikel (refereegranskat)abstract
- Infusion of human third-party mesenchymal stromal cells (MSCs) appears to be a promising therapy for acute graft-versus-host disease (aGvHD). To date, little is known about how MSCs interact with the body's innate immune system after clinical infusion. This study shows, that exposure of MSCs to blood type ABO-matched human blood activates the complement system, which triggers complement-mediated lymphoid and myeloid effector cell activation in blood. We found deposition of complement component C3-derived fragments iC3b and C3dg on MSCs and fluid-phase generation of the chemotactic anaphylatoxins C3a and C5a. MSCs bound low amounts of immunoglobulins and lacked expression of complement regulatory proteins MCP (CD46) and DAF (CD55), but were protected from complement lysis via expression of protectin (CD59). Cell-surface-opsonization and anaphylatoxin-formation triggered complement receptor 3 (CD11b/CD18)-mediated effector cell activation in blood. The complement-activating properties of individual MSCs were furthermore correlated with their potency to inhibit PBMC-proliferation in vitro, and both effector cell activation and the immunosuppressive effect could be blocked either by using complement inhibitor Compstatin or by depletion of CD14/CD11b-high myeloid effector cells from mixed lymphocyte reactions. Our study demonstrates for the first time a major role of the complement system in governing the immunomodulatory activity of MSCs and elucidates how complement activation mediates the interaction with other immune cells.
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