The antitumor effect of mesenchymal stem cells transduced with a lentiviral vector expressing cytosine deaminase in a rat glioma model

BackgroundImmunotherapy with IFNβ is a promising strategy for treating malignant glioma. However, systemic administration of IFNβ is inadequate because of low intratumoral concentration and major adverse effects. This study aimed to determine whether mesenchymal stem cells (MSCs) can be used as cellular vehicles to locally deliver IFNβ for glioma therapy by using in vivo MRI tracking.MethodsA recombinant lentiviral vector encoding IFNβ and ferritin heavy chain (FTH) reporter genes was constructed to transduce MSCs. The effectiveness and safety of transduction were assessed. After the IFNβ and FTH overexpressed MSCs (IFNβ-FTH-MSCs) were transplanted into intracranial orthotopic rat F98 gliomas via peritumoral, intracerebral, intratumoral or intra-arterial injection, MRI was performed to track IFNβ-FTH-MSCs and to evaluate their therapeutic effect on glioma in vivo, as validated by histologic analysis, quantitative PCR and ELISA assays.ResultsMSCs were efficiently and safely transduced to upregulate their IFNβ secretion and FTH expression by the constructed lentivirus. After peritumoral injection, IFNβ-FTH-MSCs appeared as hypointense signals on MRI, which gradually diminished but remained visible until 11 days. Compared with other administration routes, only peritumoral injection of IFNβ-FTH-MSCs showed a remarkable inhibition on the glioma growth. Nearly 30% of IFNβ-FTH-MSCs survived up to 11 days after peritumoral injection, while most of IFNβ-FTH-MSCs injected via other routes died within 11 days. IFNβ-FTH-MSCs grafted peritumorally secreted IFNβ persistently, leading to pronounced Batf3+dendritic cells and CD8+T lymphocyte infiltration within the glioma.ConclusionsMSCs can be used as cellular vehicles of IFNβ to treat malignant glioma effectively via peritumoral injection.

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Cytosine deaminase-producing human mesenchymal stem cells mediate an antitumor effect in a mouse xenograft model

Journal of Gastroenterology and Hepatology ◽

10.1111/j.1440-1746.2009.05862.x ◽

2009 ◽

Vol 24 (8) ◽

pp. 1393-1400 ◽

Cited By ~ 26

Author(s):

Mi-Hyeon You ◽

Wang-Joon Kim ◽

Wooyoung Shim ◽

Sang-Rim Lee ◽

Gwang Lee ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Antitumor Effect ◽

Cytosine Deaminase ◽

Xenograft Model ◽

Human Mesenchymal Stem Cells ◽

Mouse Xenograft ◽

Mouse Xenograft Model

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Antitumor Effect of Mesenchymal Stem Cells from Murine in Breast Cancer in Female Rats

Benha Veterinary Medical Journal ◽

10.21608/bvmj.2018.39664 ◽

2018 ◽

Vol 35 (1) ◽

pp. 369-374

Author(s):

Omayma A.R. AbouZaid ◽

Laila A Rashed ◽

S. M. El-Sonbaty ◽

Aboel-Ftouh A. I

Keyword(s):

Breast Cancer ◽

Stem Cells ◽

Mesenchymal Stem Cells ◽

Antitumor Effect ◽

Female Rats

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Antitumor effect of IL-12 gene-modified bone marrow mesenchymal stem cells combined with Fuzheng Yiliu decoction in an in vivo glioma nude mouse model

Journal of Translational Medicine ◽

10.1186/s12967-021-02809-2 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Jianjun Wu ◽

Shoupin Xie ◽

Hailong Li ◽

Yanxia Zhang ◽

Jia Yue ◽

...

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Mesenchymal Stem Cells ◽

Treatment Group ◽

Nude Mice ◽

Antitumor Effect ◽

Tumor Tissue ◽

Model Group ◽

Nude Mouse Model ◽

Marrow Mesenchymal Stem Cells

Abstract Background Glioma is a complex cancer with a high morbidity and high mortality. Bone marrow mesenchymal stem cells (BMSCs) have shown promise as an excellent cell/drug delivery vehicle for gene-targeted therapy; however, maintaining genetic stability and biological activity remains difficult. Furthermore, whether BMSCs support or inhibit tumor growth remains debated. This study investigated whether a traditional Chinese medicine fomular, Fuzheng Yiliu decoction (FYD) had a synergistic antitumor effect with IL-12 gene-modified BMSCs in glioma-bearing nude mice Methods The lentivirus-mediated IL-12 gene was transfected into primarily cultured BMSCs. A total of 72 BALB/c nude mice were used to establish xenograft models with glioma U251 cells and were divided into groups (n = 12) including blank control group, nude mouse model group (model group), lentiviral transfection of BMSC group with no gene loading (BMSC group), IL-12 lentivirus-transfected BMSC group (IL-12 + BMSC group), FYD treatment group (FYD group), and FYD treatment in IL-12 lentivirus-transfected BMSC group (FYD + IL-12 + BMSC group).. After treatment for 14 days, all mice were sacrificed to collect tumor tissue and serum for more detection, such as distribution of BMSCs, cell apoptosis in xenograft tumors, serum IL-12 and INF-γ levels, mouse weight and tumor volume were measured Results There were significantly more apoptotic cells in tumor tissue in IL-12 gene transfected group, FYD treatment group and FYD combining with IL-12 gene transfected group than that in the model group (P < 0.05). The FYD + IL-12 + BMSC group showed significantly higher Bax and lower Bcl-2 expression (P < 0.05), and serum IL-12 and INF-γ levels (P < 0.05) were higher than that in all other groups. After the intervention, this group also showed a strong inhibitory effect against tumor growth (P < 0.05) Conclusions This study suggested FYD treatment combined with IL-12 gene-modified BMSCs shows synergistic antitumor effect in glioma-bearing nude mice.

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CBIO-40THREE-DIMENSIONAL ASSESSMENT OF BYSTANDER EFFECTS OF MESENCHYMAL STEM CELLS CARRYING A CYTOSINE DEAMINASE GENE ON GLIOMA CELLS

Neuro-Oncology ◽

10.1093/neuonc/nov209.40 ◽

2015 ◽

Vol 17 (suppl 5) ◽

pp. v63.2-v63

Author(s):

Jin Hwa Jung ◽

Andrew Kim ◽

Da-Young Chang ◽

Sung-Soo Kim ◽

Haeyoung Suh-Kim

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Cytosine Deaminase ◽

Glioma Cells ◽

Bystander Effects ◽

Dimensional Assessment ◽

Cytosine Deaminase Gene

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Therapeutic effect of genetically engineered mesenchymal stem cells in rat experimental leptomeningeal glioma model

Cancer Letters ◽

10.1016/j.canlet.2009.10.020 ◽

2010 ◽

Vol 291 (2) ◽

pp. 256-262 ◽

Cited By ~ 20

Author(s):

Chunyu Gu ◽

Shaoyi Li ◽

Tsutomu Tokuyama ◽

Naoki Yokota ◽

Hiroki Namba

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Therapeutic Effect ◽

Genetically Engineered ◽

Glioma Model

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Effect of lentivirus-mediated growth and differentiation factor-5 transfection on differentiation of rabbit nucleus pulposus mesenchymal stem cells

European Journal of Medical Research ◽

10.1186/s40001-021-00624-5 ◽

2022 ◽

Vol 27 (1) ◽

Author(s):

Kun Zhu ◽

Rui Zhao ◽

Yuchen Ye ◽

Gang Xu ◽

Changchun Zhang

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Nucleus Pulposus ◽

Lentiviral Vector ◽

The Other ◽

Cell Phenotype ◽

Mrna Levels ◽

Qrt Pcr ◽

Differentiation Factor ◽

Gdf5 Gene

Abstract Background Intervertebral disc degeneration (IDD) is a natural progression of age-related processes. Associated with IDD, degenerative disc disease (DDD) is a pathologic condition implicated as a major cause of chronic lower back pain, which can have a severe impact on the quality of life of patients. As degeneration progression is associated with elevated levels of inflammatory cytokines, enhanced aggrecan and collagen degradation, and changes in the disc cell phenotype. The purpose of this study was to investigate the biological and cytological characteristics of rabbit nucleus pulposus mesenchymal stem cells (NPMSCs)—a key factor in IDD—and to determine the effect of the growth and differentiation factor-5 (GDF5) on the differentiation of rabbit NPMSCs transduced with a lentivirus vector. Methods An in vitro culture model of rabbit NPMSCs was established and NPMSCs were identified by flow cytometry (FCM) and quantitative real-time PCR (qRT-PCR). Subsequently, NPMSCs were randomly divided into three groups: a transfection group (the lentiviral vector carrying GDF5 gene used to transfect NPMSCs); a control virus group (the NPMSCs transfected with an ordinary lentiviral vector); and a normal group (the NPMSCs alone). FCM, qRT-PCR, and western blot (WB) were used to detect the changes in NPMSCs. Results The GDF5-transfected NPMSCs displayed an elongated shape, with decreased cell density, and significantly increased GDF5 positivity rate in the transfected group compared to the other two groups (P < 0.01). The mRNA levels of Krt8, Krt18, and Krt19 in the transfected group were significantly higher in comparison with the other two groups (P < 0.01), and the WB results were consistent with that of qRT-PCR. Conclusions GDF5 could induce the differentiation of NPMSCs. The lentiviral vector carrying the GDF5 gene could be integrated into the chromosome genome of NPMSCs and promoted differentiation of NPMSCs into nucleus pulposus cells. Our findings advance the development of feasible and effective therapies for IDD.

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Abstract 403: Tracking the Migration of Porcine Mesenchymal Stem Cells with the MRI Contrast Agent Ferex in an AAA Model

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.32.suppl_1.a403 ◽

2012 ◽

Vol 32 (suppl_1) ◽

Author(s):

Rami Tadros ◽

Bhakti Rawal ◽

Karen Briley-Saebo ◽

David O’Connor ◽

Dan Han ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Contrast Agent ◽

Lentiviral Vector ◽

Relaxation Times ◽

Mri Contrast Agent ◽

Signal Loss ◽

Post Transplantation ◽

Mri Contrast

Introduction: Mesenchymal stem cells (MSC) are being investigated in porcine abdominal aortic aneurysm (PAAA) models for their repair potential. This study uses MSCs labeled with the MRI contrast agent Ferex to non-invasively evaluate MSC migration in-vivo. Methods: MSCs from 6 pigs were isolated from bone marrow via Ficoll Paque separation and expanded in culture. Using a Lentiviral vector, MSC from all 6 pigs were transfected with green florescent protein (GFP). MSCs from 4 of these pigs were also labeled with 200μg/ml Ferex using Poly-L-Lysine and then analyzed for Ferex uptake and viability. Preservation of the MSC phenotype was confirmed using flow cytometry by detecting positive CD90 and negative CD45 and CD117. Transmission electron microscopy established that Ferex localized to lysosomes. MSCs were then injected into the adventitia of the PAAA. In-vivo MRI was performed using multiple echo gradient echo sequences. Effective transverse relaxation times (T2* values) were calculated on a pixel-by-pixel basis as a function of time post cell transplantation. Results: Ferex labeled MSCs were visible post transplantation at 4, 11, 15 and 21 days using MRI. The MRI signal void (decreased T2* values) correlated with the presence of Ferex within the PAAA. This signal loss progressively expanded circumferentially at each study interval representing cellular movement. MSC migration and localization were confirmed with GFP visualization on fluorescence microscopy and immunohistochemistry. In-vivo MRI signals also correlate with iron deposition on Perl’s stain. Conclusion: Ferex can be used as an in-vivo tracking agent of MSCs in PAAA models.

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