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Fransson, Moa
Alternative names
Publications (10 of 13) Show all publications
Ajalloueian, F., Fransson, M., Tavanai, H., Massuni, M., Hilborn, J., LeBlanc, K., . . . Magnusson, P. (2015). Investigation of Human Mesenchymal Stromal Cells Cultured on PLGA orPLGA/Chitosan Electrospun Nanofibers. Journal of Bioprocessing & Biotechniques, 5(6), Article ID 230.
Open this publication in new window or tab >>Investigation of Human Mesenchymal Stromal Cells Cultured on PLGA orPLGA/Chitosan Electrospun Nanofibers
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2015 (English)In: Journal of Bioprocessing & Biotechniques, ISSN 2155-9821, Vol. 5, no 6, article id 230Article in journal (Refereed) Published
Abstract [en]

We compared the viability, proliferation, and differentiation of human Mesenchymal Stromal Cells (MSC)after culture on poly(lactic-co-glycolic acid) (PLGA) and PLGA/chitosan (PLGA/CH) hybrid scaffolds. We appliedconventional and emulsion electrospinning techniques, respectively, for the fabrication of the PLGA and PLGA/CH scaffolds. Electrospinning under optimum conditions resulted in an average fiber diameter of 166 ± 33 nmfor the PLGA/CH and 680 ± 175 nm for the PLGA scaffold. The difference between the tensile strength of thePLGA and PLGA/CH nanofibers was not significant, but PLGA/CH showed a significantly lower tensile modulusand elongation at break. However, it should be noted that the extensibility of the PLGA/CH was higher than thatof the nanofibrous scaffolds of pure chitosan. As expected, a higher degree of hydrophilicity was seen with PLGA/CH, as compared to PLGA alone. The biocompatibility of the PLGA and PLGA/CH scaffolds was compared usingMTS assay as well as analysis by scanning electron microscopy and confocal microscopy. The results showed thatboth scaffold types supported the viability and proliferation of human MSC, with significantly higher rates on PLGA/CH nanofibers. Nonetheless, an analysis of gene expression of MSC grown on either PLGA or PLGA/CH showed asimilar differentiation pattern towards bone, nerve and adipose tissues.

Keywords
Electrospinning; PLGA; Chitosan; Synthetic-natural scaffold; Mesenchymal stromal cells; Viability; Proliferation
National Category
Medical Biotechnology
Identifiers
urn:nbn:se:uu:diva-276981 (URN)10.4172/2155-9821.1000230 (DOI)
Available from: 2016-02-16 Created: 2016-02-16 Last updated: 2018-05-23Bibliographically approved
Fransson, M., Brännström, J., Duprez, I., Essand, M., Le Blanc, K., Korsgren, O. & Magnusson, P. (2015). Mesenchymal stromal cells supportendothelial cell interactions in anintramuscular islet transplantation model. Regenerative Medicine Research, 3, Article ID UNSP 1.
Open this publication in new window or tab >>Mesenchymal stromal cells supportendothelial cell interactions in anintramuscular islet transplantation model
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2015 (English)In: Regenerative Medicine Research, ISSN 2050-490X, Vol. 3, article id UNSP 1Article in journal (Refereed) Published
Abstract [en]

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.

Keywords
Mesenchymal stromal cell, endothelial cells, islets of Langerhans, transplantation
National Category
Clinical Medicine
Identifiers
urn:nbn:se:uu:diva-276979 (URN)10.1186/s40340-015-0010-9 (DOI)000363658500001 ()
Available from: 2016-02-16 Created: 2016-02-16 Last updated: 2017-01-25Bibliographically approved
Burman, J., Zetterberg, H., Fransson, M., Loskog, A. S., Raininko, R. & Fagius, J. (2014). Assessing tissue damage in multiple sclerosis: a biomarker approach. Acta Neurologica Scandinavica, 130(2), 81-89
Open this publication in new window or tab >>Assessing tissue damage in multiple sclerosis: a biomarker approach
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2014 (English)In: Acta Neurologica Scandinavica, ISSN 0001-6314, E-ISSN 1600-0404, Vol. 130, no 2, p. 81-89Article in journal (Refereed) Published
Abstract [en]

OBJECTIVES:

Magnetic resonance imaging (MRI) of the brain and spinal cord is the gold standard for assessing disease activity in multiple sclerosis (MS). MRI is an excellent instrument for determination of accumulated damage to the brain and spinal cord, but tells us little about ongoing tissue damage. In this study, biomarkers of oligodendrocyte, axonal and astrocyte injury were related to MRI and clinical findings and used to assess tissue damage in MS.

MATERIALS AND METHODS:

Cerebrospinal fluid from 44 patients with relapsing-remitting MS, 20 with secondary progressive MS and 15 controls were investigated with ELISA to determine levels of myelin basic protein (MBP), neurofilament light (NFL) and glial fibrillary acidic protein (GFAp). Patients underwent MRI of the brain and spinal cord, and gadolinium enhancing lesions, T1 lesions and T2 lesions were counted.

RESULTS:

Patients in clinical relapse and patients with nonsymptomatic gadolinium enhancing lesions had high levels of MBP and NFL, indicating ongoing damage to oligodendrocytes and axons. The level of MBP dropped quickly within a week from the onset of a relapse, whereas NFL remained elevated for several weeks and GFAp slowly rose during the course of a relapse. Relapsing-remitting MS patients without gadolinium enhancing lesions had values of MBP, NFL and GFAp similar to controls, while patients with secondary progressive disease had moderately increased values of all biomarkers.

CONCLUSIONS:

Analysis of MBP, NFL and GFAp provides direct means to measure tissue damage and is a useful addition to our methods for evaluation of MS.

National Category
Neurosciences Neurology
Research subject
Clinical Immunology
Identifiers
urn:nbn:se:uu:diva-219571 (URN)10.1111/ane.12239 (DOI)000339951900006 ()24571714 (PubMedID)
Available from: 2014-03-04 Created: 2014-03-04 Last updated: 2018-01-11Bibliographically approved
Fransson, M., Piras, E., Wang, H., Burman, J., Duprez, I., Harris, R. A., . . . Loskog, A. S. (2014). Intranasal Delivery of CNS-Retargeted Human Mesenchymal Stromal Cells Prolongs Treatment Efficacy of Experimental Autoimmune Encephalomyelitis. Immunology, 142(3), 431-441
Open this publication in new window or tab >>Intranasal Delivery of CNS-Retargeted Human Mesenchymal Stromal Cells Prolongs Treatment Efficacy of Experimental Autoimmune Encephalomyelitis
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2014 (English)In: Immunology, ISSN 0019-2805, E-ISSN 1365-2567, Vol. 142, no 3, p. 431-441Article in journal (Refereed) Published
Abstract [en]

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.

National Category
Immunology
Identifiers
urn:nbn:se:uu:diva-223631 (URN)10.1111/imm.12275 (DOI)000337600500012 ()24588452 (PubMedID)
Note

De två första författarna delar förstaförfattarskapet.

Available from: 2014-04-23 Created: 2014-04-23 Last updated: 2018-05-18Bibliographically approved
Burman, J., Svensson, E., Fransson, M., Loskog, A. S., Zetterberg, H., Raininko, R., . . . Mangsbo, S. M. (2014). The cerebrospinal fluid cytokine signature of multiple sclerosis: A homogenous response that does not conform to the Th1/Th2/Th17 convention. Journal of Neuroimmunology, 277(1-2), 153-159
Open this publication in new window or tab >>The cerebrospinal fluid cytokine signature of multiple sclerosis: A homogenous response that does not conform to the Th1/Th2/Th17 convention
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2014 (English)In: Journal of Neuroimmunology, ISSN 0165-5728, E-ISSN 1872-8421, Vol. 277, no 1-2, p. 153-159Article in journal (Refereed) Published
Abstract [en]

In this cross-sectional study, we wanted to identify key cytokines characteristic of different stages of multiple sclerosis (MS). To this end, cerebrospinal fluid from patients with MS was investigated with a multiplexed fluorescent bead-based immunoassay. In total 43 cytokines were assessed and related to clinical and imaging data. Increased levels of CCL22, CXCL10 and sCD40L characterized relapsing-remitting MS patients with the presence of gadolinium-enhancing lesions; decreased CCL2 and increased CXCL1 and CCL5 were typical of relapsing-remitting MS patients irrespectively of the presence of gadolinium-enhancing lesions. These homogenous patterns of cytokine activation do not conform to conventional Th1/Th2/Th17 responses.

National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-239312 (URN)10.1016/j.jneuroim.2014.10.005 (DOI)000347663100019 ()25457841 (PubMedID)
Available from: 2014-12-22 Created: 2014-12-22 Last updated: 2017-12-05Bibliographically approved
Burman, J., Svensson, E., Fransson, M., Loskog, A. & Mangsbo, S. (2014). Tim-3 and PD-1: Regulators of adaptive immunity in multiple sclerosis. Paper presented at 12th International Congress of Neuroimmunology (ISNI), NOV 09-13, 2014, Mainz, GERMANY. Journal of Neuroimmunology, 275(1-2), 141-141
Open this publication in new window or tab >>Tim-3 and PD-1: Regulators of adaptive immunity in multiple sclerosis
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2014 (English)In: Journal of Neuroimmunology, ISSN 0165-5728, E-ISSN 1872-8421, Vol. 275, no 1-2, p. 141-141Article in journal, Meeting abstract (Other academic) Published
National Category
Immunology in the medical area Neurology
Identifiers
urn:nbn:se:uu:diva-240853 (URN)10.1016/j.jneuroim.2014.08.378 (DOI)000345192100368 ()
Conference
12th International Congress of Neuroimmunology (ISNI), NOV 09-13, 2014, Mainz, GERMANY
Available from: 2015-01-08 Created: 2015-01-08 Last updated: 2018-01-11Bibliographically approved
Karlsson, S. C., Lindqvist, A. C., Fransson, M., Paul-Wetterberg, G., Nilsson, B., Essand, M., . . . Loskog, S. I. (2013). Combining CAR T cells and the Bcl-2 family apoptosis inhibitor ABT-737 for treating B-cell malignancy. Cancer Gene Therapy, 20(7), 386-393
Open this publication in new window or tab >>Combining CAR T cells and the Bcl-2 family apoptosis inhibitor ABT-737 for treating B-cell malignancy
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2013 (English)In: Cancer Gene Therapy, ISSN 0929-1903, E-ISSN 1476-5500, Vol. 20, no 7, p. 386-393Article in journal (Refereed) Published
Abstract [en]

B-cell malignancies upregulate the B-cell lymphoma 2 (Bcl-2) family inhibitors of the intrinsic apoptosis pathway, making them therapy resistant. However, small-molecule inhibitors of Bcl-2 family members such as ABT-737 restore a functional apoptosis pathway in cancer cells, and its oral analog ABT-263 (Navitoclax) has entered clinical trials. Gene engineered chimeric antigen receptor (CAR) T cells also show promise in B-cell malignancy, and as they induce apoptosis via the extrinsic pathway, we hypothesized that small-molecule inhibitors of the Bcl-2 family may potentiate the efficacy of CAR T cells by engaging both apoptosis pathways. CAR T cells targeting CD19 were generated from healthy donors as well as from pre-B-ALL (precursor-B acute lymphoblastic leukemia) patients and tested together with ABT-737 to evaluate apoptosis induction in five B-cell tumor cell lines. The CAR T cells were effective even if the cell lines exhibited different apoptosis resistance profiles, as shown by analyzing the expression of apoptosis inhibitors by PCR and western blot. When combining T-cell and ABT-737 therapy simultaneously, or with ABT-737 as a presensitizer, tumor cell apoptosis was significantly increased. In conclusion, the apoptosis inducer ABT-737 enhanced the efficacy of CAR T cells and could be an interesting drug candidate to potentiate T-cell therapy.

Keywords
ABT-737, BH3 mimetics, engineered T cells, CAR, Bcl-2, pre-B-ALL
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-204980 (URN)10.1038/cgt.2013.35 (DOI)000321951700002 ()
Available from: 2013-08-16 Created: 2013-08-13 Last updated: 2019-12-14Bibliographically approved
Burman, J., Fransson, M., Tötterman, T. H., Fagius, J., Mangsbo, S. M. & Loskog, A. S. I. (2013). T-cell responses after haematopoietic stem cell transplantation for aggressive relapsing-remitting multiple sclerosis. Immunology, 140(2), 211-219
Open this publication in new window or tab >>T-cell responses after haematopoietic stem cell transplantation for aggressive relapsing-remitting multiple sclerosis
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2013 (English)In: Immunology, ISSN 0019-2805, E-ISSN 1365-2567, Vol. 140, no 2, p. 211-219Article in journal (Refereed) Published
Abstract [en]

Autologous haematopoietic stem cell transplantation (HSCT) for relapsing-remitting multiple sclerosis is a potentially curative treatment, which can give rise to long-term disease remission. However, the mode of action is not yet fully understood. The aim of the study was to evaluate similarities and differences of the CD4(+) T-cell populations between HSCT-treated patients (n = 12) and healthy controls (n = 9). Phenotyping of memory T cells, regulatory T (Treg) cells and T helper type 1 (Th1) and type 17 (Th17) cells was performed. Further, T-cell reactivity to a tentative antigen, myelin oligodendrocyte glycoprotein, was investigated in these patient populations. Patients treated with natalizumab (n = 15) were included as a comparative group. White blood cells were analysed with flow cytometry and T-cell culture supernatants were analysed with magnetic bead panel immunoassays. HSCT-treated patients had similar levels of Treg cells and of Th1 and Th17 cells as healthy subjects, whereas natalizumab-treated patients had lower frequencies of Treg cells, and higher frequencies of Th1 and Th17 cells. Cells from HSCT-treated patients cultured with overlapping peptides from myelin oligodendrocyte glycoprotein produced more transforming growth factor-beta(1) than natalizumab-treated patients, which suggests a suppressive response. Conversely, T cells from natalizumab-treated patients cultured with those peptides produced more interleukin-17 (IL-17), IL-1 and IL-10, indicating a Th17 response. In conclusion, we demonstrate circumstantial evidence for the removal of autoreactive T-cell clones as well as development of tolerance after HSCT. These results parallel the long-term disease remission seen after HSCT.

Keywords
haematopoietic stem cell transplantation, multiple sclerosis, natalizumab, neuroimmunology
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-211463 (URN)10.1111/imm.12129 (DOI)000324303200007 ()
Available from: 2013-11-25 Created: 2013-11-25 Last updated: 2017-12-06Bibliographically approved
Fransson, M., Piras, E., Burman, J., Nilsson, B., Essand, M., Lu, B., . . . Loskog, A. S. (2012). CAR/FoxP3-engineered T regulatory cells target the CNS and suppress EAE upon intranasal delivery. Journal of Neuroinflammation, 9, 112
Open this publication in new window or tab >>CAR/FoxP3-engineered T regulatory cells target the CNS and suppress EAE upon intranasal delivery
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2012 (English)In: Journal of Neuroinflammation, ISSN 1742-2094, E-ISSN 1742-2094, Vol. 9, p. 112-Article in journal (Refereed) Published
Abstract [en]

BACKGROUND:

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS). In the murine experimental autoimmune encephalomyelitis (EAE) model of MS, T regulatory (Treg) cell therapy has proved to be beneficial, but generation of stable CNS-targeting Tregs needs further development. Here, we propose gene engineering to achieve CNS-targeting Tregs from naive CD4 cells and demonstrate their efficacy in the EAE model.

METHODS

CD4+T cells were modified utilizing a lentiviral vector system to express a chimeric antigen receptor (CAR) targeting myelin oligodendrocyte glycoprotein (MOG) in trans with the murine FoxP3 gene that drives Treg differentiation. The cells were evaluated in vitro for suppressive capacity and in C57BL/6 mice to treat EAE. Cells were administered by intranasal (i.n.) cell delivery.

RESULTS

The engineered Tregs demonstrated suppressive capacity in vitro and could efficiently access various regions in the brain via i.n cell delivery. Clinical score 3 EAE mice were treated and the engineered Tregs suppressed ongoing encephalomyelitis as demonstrated by reduced disease symptoms as well as decreased IL-12 and IFNgamma mRNAs in brain tissue. Immunohistochemical markers for myelination (MBP) and reactive astrogliosis (GFAP) confirmed recovery in mice treated with engineered Tregs compared to controls. Symptomfree mice were echallenged with a second EAE-inducing inoculum but remained healthy, demonstrating the sustained effect of engineered Tregs.

CONCLUSION

CNS-targeting Tregs delivered i.n. localized to the CNS and efficiently suppressed ongoing inflammation leading to diminished disease symptoms.

Keywords
MS, redirected cells, T regulatory cells, EAE, FoxP3, myelin oligodendrocyte glycoprotein
National Category
Neurology
Research subject
Neurology
Identifiers
urn:nbn:se:uu:diva-175383 (URN)10.1186/1742-2094-9-112 (DOI)000307014500001 ()22647574 (PubMedID)
Note

De två första författarna delar första författarskapet.

Available from: 2012-06-05 Created: 2012-06-05 Last updated: 2018-05-18Bibliographically approved
Fransson, M. (2010). CNS-Targeted Cell Therapy for Multiple Sclerosis. (Doctoral dissertation). Uppsala: Acta Universitatis Upsaliensis
Open this publication in new window or tab >>CNS-Targeted Cell Therapy for Multiple Sclerosis
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Multiple sclerosis (MS) is an autoimmune disorder of the central nervous system (CNS). In the current thesis, we have preformed an immunological investigation of patients with MS and developed an immunosuppressive cell therapy that could be beneficial for these patients.

MS has been considered to be driven by T helper type1 (Th1) lymphocytes but new data indicate the involvement of Th17 responses. T cells from patients with MS that were evaluated for immunological status secreted both interferon-γ and interleukin-17 upon stimulation. However, T cells from patients with MS in remission, in contrast to relapse, had poor proliferative capacity suggesting that they are controlled and kept in anergy.

T regulatory cells (Tregs) are important to maintain self-tolerance and the role of CD4+CD25+FoxP3+ Tregs in autoimmunity has been extensively investigated. We analyzed Tregs from patients with MS in relapse and remission by multicolor flow cytometry for the expression of CD3, CD4, IL2R (CD25), FoxP3 and the IL7R (CD127). Patients in relapse exhibited higher levels of FoxP3-positive Tregs lacking CD25 compared to healthy controls, indicating that Tregs might attempt to restrain immune activity during relapse.

In the murine experimental autoimmune encephalomyelitis (EAE) model of MS, therapy with suppressive cells such as Tregs or mesenchymal stromal cells (MSCs) has proven beneficial. However, systemic administration of such cells may immunologically compromise the recipient and promote infections due to general immunosuppression. We hypothesized that suppressive cells can be equipped with a CNS-targeting receptor and be delivered intra-nasally to avoid systemic exposure. CD4+ T cells were modified with a lentiviral vector system to express a myelin oligodendrocyte (MOG)-targeting receptor in trans with the FoxP3 gene that drives Treg differentiation. Genetically engineered Tregs demonstrated suppressive capacity in vitro and localized to the brain and suppressed ongoing encephalomyelitis in vivo. Cured mice were rechallenged with an EAE-inducing inoculum but remained healthy.

MSCs are a heterogeneous population of stromal cells residing in most connective tissues and have the capacity to suppress effector cells of the immune system. MSCs were engineered to express MOG-targeting receptors using lentiviral vectors. Genetically engineered MSCs retained their suppressive capacity in vitro and successfully targeted the brain upon intranasal delivery. Engineered MSCs cured mice from disease symptoms and these mice were resistant to further EAE challenge. Encephalitic T cells isolated from cured mice displayed an anergic profile while peripheral T cells were still responsive to stimuli.

In conclusion, MS patients have peripheral CNS-reactive T cells of both Th1 and Th17 type that, while in remission, are kept in anergy. Also, MS patients in relapse exhibit increased levels of CD25 negative Tregs indicating an attempt to restrain immune activity. Finally, immunosuppressive cells can be genetically engineered to target CNS and efficiently suppress encephalomyelitis in an active EAE model upon intranasal delivery.

 

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2010. p. 59
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 608
Keywords
CAR, Targeting, Suppressive cells, Foxp3, Tregs
National Category
Immunology in the medical area
Research subject
Immunology
Identifiers
urn:nbn:se:uu:diva-132364 (URN)978-91-554-7918-3 (ISBN)
Public defence
2010-12-03, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjöldsväg 20, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2010-11-12 Created: 2010-10-19 Last updated: 2018-01-12Bibliographically approved
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