Suicide Gene Therapy Against Malignant Gliomas by the Local Delivery of Genetically Engineered Umbilical Cord Mesenchymal Stem Cells as Cellular Vehicles

Background: Glioblastoma (GBM) is a malignant tumor that is difficult to eliminate, and new therapies are thus strongly desired. Mesenchymal stem cells (MSCs) have the ability to locate to injured tissues, inflammation sites and tumors and are thus good candidates for carrying antitumor genes for the treatment of tumors. Treating GBM with MSCs that have been transduced with the herpes simplex virus thymidine kinase (HSV-TK) gene has brought significant advances because MSCs can exert a bystander effect on tumor cells upon treatment with the prodrug ganciclovir (GCV). Objective: In this study, we aimed to determine whether HSV-TK-expressing umbilical cord mesenchymal stem cells (MSCTKs) together with prodrug GCV treatment could exert a bystander killing effect on GBM. Methods and Results: Compared with MSCTK: U87 ratio at 1:10,1:100 and 1:100, GCV concentration at 2.5µM or 250µM, when MSCTKs were cocultured with U87 cells at a ratio of 1:1, 25 µM GCV exerted a more stable killing effect. Higher amounts of MSCTKs cocultured with U87 cells were correlated with a better bystander effect exerted by the MSCTK/GCV system. We built U87-driven subcutaneous tumor models and brain intracranial tumor models to evaluate the efficiency of the MSCTK/GCV system on subcutaneous and intracranial tumors and found that MSCTK/GCV was effective in both models. The ratio of MSCTKs and tumor cells played a critical role in this therapeutic effect, with a higher MSCTK/U87 ratio exerting a better effect. Conclusion: This research suggested that the MSCTK/GCV system exerts a strong bystander effect on GBM tumor cells, and this system may be a promising assistant method for GBM postoperative therapy.

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Overexpression of Pygo2 Increases Differentiation of Human Umbilical Cord Mesenchymal Stem Cells into Cardiomyocyte-like Cells

Current Molecular Medicine ◽

10.2174/1566524019666191017150416 ◽

2020 ◽

Vol 20 (4) ◽

pp. 318-324 ◽

Cited By ~ 3

Author(s):

Lei Yang ◽

Shuoji Zhu ◽

Yongqing Li ◽

Jian Zhuang ◽

Jimei Chen ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Umbilical Cord ◽

Heart Function ◽

Critical Role ◽

Human Umbilical Cord ◽

Stem Cell Markers ◽

Quantitative Real Time Pcr ◽

Qrt Pcr

Background: Our previous studies have shown that Pygo (Pygopus) in Drosophila plays a critical role in adult heart function that is likely conserved in mammals. However, its role in the differentiation of human umbilical cord mesenchymal stem cells (hUC-MSCs) into cardiomyocytes remains unknown. Objective: To investigate the role of pygo2 in the differentiation of hUC-MSCs into cardiomyocytes. Methods: Third passage hUC-MSCs were divided into two groups: a p+ group infected with the GV492-pygo2 virus and a p− group infected with the GV492 virus. After infection and 3 or 21 days of incubation, Quantitative real-time PCR (qRT-PCR) was performed to detect pluripotency markers, including OCT-4 and SOX2. Nkx2.5, Gata-4 and cTnT were detected by immunofluorescence at 7, 14 and 21 days post-infection, respectively. Expression of cardiac-related genes—including Nkx2.5, Gata-4, TNNT2, MEF2c, ISL-1, FOXH1, KDR, αMHC and α-Actin—were analyzed by qRT-PCR following transfection with the virus at one, two and three weeks. Results : After three days of incubation, there were no significant changes in the expression of the pluripotency stem cell markers OCT-4 and SOX2 in the p+ group hUC-MSCs relative to controls (OCT-4: 1.03 ± 0.096 VS 1, P > 0.05, SOX2: 1.071 ± 0.189 VS 1, P > 0.05); however, after 21 days, significant decreases were observed (OCT-4: 0.164 ± 0.098 VS 1, P < 0.01, SOX2: 0.209 ± 0.109 VS 1, P < 0.001). Seven days following incubation, expression of mesoderm specialisation markers, such as Nkx2.5, Gata-4, MEF2c and KDR, were increased; at 14 days following incubation, expression of cardiac genes, such as Nkx2.5, Gata-4, TNNT2, MEF2c, ISL-1, FOXH1, KDR, αMHC and α-Actin, were significantly upregulated in the p+ group relative to the p− group (P < 0.05). Taken together, these findings suggest that overexpression of pygo2 results in more hUCMSCs gradually differentiating into cardiomyocyte-like cells. Conclusion: We are the first to show that overexpression of pygo2 significantly enhances the expression of cardiac-genic genes, including Nkx2.5 and Gata-4, and promotes the differentiation of hUC-MSCs into cardiomyocyte-like cells.

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p38 MAPK Contributes to the Growth Inhibition of Leukemic Tumor Cells Mediated by Human Umbilical Cord Mesenchymal Stem Cells

Cellular Physiology and Biochemistry ◽

10.1159/000323973 ◽

2010 ◽

Vol 26 (6) ◽

pp. 799-808 ◽

Cited By ~ 27

Author(s):

Kun Tian ◽

Shaoguang Yang ◽

Qian Ren ◽

Zhibo Han ◽

Shihong Lu ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Growth Inhibition ◽

Tumor Cells ◽

P38 Mapk ◽

Umbilical Cord ◽

Human Umbilical Cord

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STEM-08. GENE THERAPY USING IL-24-EXPRESSING UMBILICAL CORD-DERIVED MESENCHYMAL STEM CELLS AGAINST GLIOMA

Neuro-Oncology ◽

10.1093/neuonc/noz175.982 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi235-vi235

Author(s):

Shaochen Fan ◽

Yilu Gao

Keyword(s):

Stem Cells ◽

Gene Therapy ◽

Mesenchymal Stem Cells ◽

Stem Cell ◽

Tumor Cells ◽

Umbilical Cord ◽

Targeted Delivery ◽

High Dose ◽

Inhibition Of Proliferation ◽

Cell Based Therapy

Abstract Despite many advances have been made in treatment of gliomas, patients prognosis remains poor. Stem cell-based therapy has been thought to be a promising option for gliomas and many studies have reported that umbilical cord-derived mesenchymal stem cells (UC-MSCs) are ideal gene vectors for tumor gene therapy. Interleukin 24 (IL-24) is a pleiotropic immunoregulatory cytokine which has an apoptotic effect on many kinds of tumor cells and can inhibit the growth of tumors specifically without damaging normal cells. However, there are still some challenges in its clinical application, such as the half-life, toxicity caused by high-dose application, and so on. Therefore, we hypothesize that combination of gene transfer with stem cell transplantation could overcome the problems. In this study, we investigated UC-MSCs transduced with lentiviral vectors carrying IL-24 complementary DNA as a vehicle for the targeted delivery of IL-24 to local tumor sites. The engineered UC-MSCs selectively migrated to glioma cells and showed the antitumor effect in vitro and in vivo. The restrictive efficacy of these UC-MSCs was related to the inhibition of proliferation and induction of apoptosis in tumor cells. These findings indicate that UC-MSCs-based IL-24 gene therapy can obviously suppress the growth of glioma xenografts, thereby suggesting the potential for future therapeutic interventions in the treatment of gliomas. Keywords: Glioma, Gene therapy, Umbilical cord-derived mesenchymal stem cells (UC-MSCs), Interleukin 24 (IL-24)

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Inhibition of glioblastoma cell invasion by hsa-miR-145-5p and hsa-miR-31-5p co-overexpression in human mesenchymal stem cells

Journal of Neurosurgery ◽

10.3171/2017.8.jns1788 ◽

2018 ◽

Vol 130 (1) ◽

pp. 44-55 ◽

Cited By ~ 5

Author(s):

Ryota Kurogi ◽

Akira Nakamizo ◽

Satoshi O. Suzuki ◽

Masahiro Mizoguchi ◽

Koji Yoshimoto ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Cell Invasion ◽

Glioma Cell ◽

Malignant Gliomas ◽

Brain Slices ◽

Glioma Cells ◽

Dependent Manner ◽

Study Results ◽

U87 Cells

OBJECTIVEHuman bone marrow–derived mesenchymal stem cells (hMSCs) show tropism for brain tumors and may be a useful vehicle for drug or gene delivery to malignant gliomas. Recently, some microRNAs (miRNAs) have been shown to suppress the invasiveness of malignant gliomas.METHODSTo test their potential to become vehicles for the delivery of miRNA to malignant gliomas, hMSCs were engineered so that hMSC secretion of miRNAs that inhibit glioma cell invasion was enabled without altering the hMSC tropism for glioma cells.RESULTSIn coculture, hMSCs cotransfected with hsa-miR-145-5p and -31-5p miRNAs showed markedly reduced invasion by U87 glioma cells in a contact-dependent manner both in vitro and ex vivo, with invasion of hMSCs cotransfected with these 2 miRNAs by the U87 cells reduced to 60.7% compared with control cells. According to a Matrigel invasion assay, the tropism of the hMSCs for U87 cells was not affected. In glioma cell lines U251 and LN229, hMSCs exhibited tropism in vivo, and invasion of hMSCs cotransfected with hsa-miR-145-5p and -31-5p was also significantly less than that of control cells. When U87 cells were coimplanted into the striatum of organotypic rat brain slices with hMSCs cotransfected with hsa-miR-145 and -31-5p, the relative invasive area decreased by 37.1%; interestingly, these U87 cells showed a change to a rounded morphology that was apparent at the invasion front. Whole-genome microarray analysis of the expression levels of 58,341 genes revealed that the co-overexpression of hsa-miR-145-5p and -31-5p downregulated FSCN1 expression in U87 cells.CONCLUSIONSThis study demonstrates that miRNA overexpression in hMSCs can alter the function of glioma cells via contact-dependent transfer. Co-overexpression of multiple miRNAs may be a useful and novel therapeutic strategy. The study results suggest that hMSCs can be applied as a delivery vehicle for miRNAs.

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