Shu Wang
Email Address
dbsws@nus.edu.sg
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Publication Antisense inhibition of BCL-2 expression induces retinoic acid-mediated cell death during differentiation of human NT2N neurons(2001) Wang, S.; Rosengren, L.E.; Hamberger, A.; Haglid, K.G.; BIOENGINEERINGChanges in expression of the proto-oncogene Bcl-2 are well known in the developing brain, with a high expression level in young post-mitotic neurons that are beginning the outgrowth of processes. The physiological significance of the Bcl-2 up-regulation in these neurons is not fully understood. We used a differentiation model for human CNS neurons to study the expression and function of Bcl-2. NT2/D1 human neuronal precursor cells differentiated into a neuronal phenotype in the presence of 10 μM retinoic acid for 3-5 weeks. This concentration of retinoic acid was not toxic to undifferentiated NT2/D1 cells but was sufficient to up-regulate the BCL-2 protein in 6 days. The BCL-2 levels increased further after 3 weeks, i.e. when the cells started to show neuronal morphology. Inhibition of the accumulation of endogenous BCL-2 with vectors expressing the antisense mRNA of Bcl-2 caused extensive apoptosis after 3 weeks of the retinoic acid treatment. The loss of neuron-like cells from differentiating cultures indicated that the dead cells were those committed to neuronal differentiation. Death was related to the presence of retinoic acid since withdrawal of retinoic acid after 16 days of treatment dramatically increased cell surviving. The ability of BCL-2 to prevent retinoic acid-induced cell death was also confirmed in undifferentiated NT2/D1 cells that were transfected with a vector containing Bcl-2 cDNA in sense orientation and exposed to toxic doses (40-80 μM) of retinoic acid. Furthermore, down-regulation of BCL-2 levels by an antisense oligonucleotide in neuronally differentiated NT2/D1 cells increased their susceptibility to retinoic acid-induced apoptosis. These results indicate that one function of the up-regulation of endogenous BCL-2 during neuronal differentiation is to regulate the sensitivity of young post-mitotic neurons to retinoic acid-mediated apoptosis.Publication Antiglioma effects of combined use of a baculovirual vector expressing wild-type p53 and sodium butyrate(2011-01) Guo, H.; Choudhury, Y.; Yang, J.; Chen, C.; Tay, F.C.; Lim, T.M.; Wang, S.; BIOLOGICAL SCIENCESBackground: Combination therapy is usually desirable for successful cancer treatment, especially in cancers that are resistant to single forms of therapy. +Methods: To achieve an optimal therapeutic effect against glioblastoma, we tested a strategy that combines baculovirus-mediated transfer of the p53 tumor suppressor gene with the use of sodium butyrate, a histone deacetylase inhibitor. This strategy was designed based on the findings that the transduction efficiency of baculovirus in mammalian cells can be markedly enhanced by the addition of histone deacetylase inhibitors and that these inhibitors are effective in inducing cell cycle arrest, differentiation, or apoptosis in tumor cells. +Results: We observed a synergistic effect of the combination of the two treatments in provoking apoptosis in glioblastoma cells with mutant p53. In a mouse glioma xenograft model, the tumor inhibitory effect of baculovirus-expressed p53 was significantly enhanced by co-administration of sodium butyrate. +Conclusions: These findings suggest a new approach to treat glioblastoma using baculovirus-mediated gene transfer in combination with administration of histone deacetylase inhibitor. © 2010 John Wiley & Sons, Ltd.Publication Targeted suicide gene therapy for glioma using human embryonic stem cell-derived neural stem cells genetically modified by baculoviral vectors(2012-02) Zhao, Y.; Lam, D.H.; Yang, J.; Lin, J.; Tham, C.K.; Ng, W.H.; Wang, S.; BIOLOGICAL SCIENCESTumor-tropic neural stem cells (NSCs) can be used in the Trojan horse approach as cellular vehicles for targeted delivery of therapeutic agents to distant tumor sites. To realize this cancer therapy potential, it is important to have a renewable source to generate large quantities of uniform human NSCs. Here, we reported that NSCs derived from HES1 human embryonic stem cell line were capable of migrating into intracranial glioma xenografts after systemic injection or after intracranial injection at a site distant from the tumor. To test whether the HES1-derived NSCs can be used for cancer gene therapy, we used a baculoviral vector to introduce the herpes simplex virus thymidine kinase suicide gene into the cells and demonstrated that baculovirus-mediated transgene expression may last for at least 3 weeks in NSCs. After being injected into the cerebral hemisphere opposite the tumor site and in the presence of ganciclovir, NSCs expressing the suicide gene were able to inhibit the growth of human glioma xenografts and prolong survival of tumor-bearing mice. Our findings suggest that human embryonic stem cells could potentially serve as a clinically viable source for production of cellular vehicles suitable for targeted anticancer gene therapy. © 2012 Macmillan Publishers Limited All rights reserved.Publication GPS2Vec: Towards generating worldwide GPS embeddings(ACM, 2019-11-05) Yin, Y; Liu, Z; Zhang, Y; Wang, S; Shah, RR; Zimmermann, R; Dr Yifang Yin; CHEMICAL & BIOMOLECULAR ENGINEERINGGPS coordinates are fine-grained location indicators that are difficult to be effectively utilized by classifiers in geo-aware applications. Previous GPS embedding methods are mostly tailored for specific problems that are taken place within areas of interest. When it comes to the scale of the entire planet, existing approaches always suffer from extensive computational cost and significant information loss. To solve these issues, we present a novel two-level grid based framework to learn semantic embeddings for geo-coordinates worldwide. The Earth's surface is first discretized by the Universal Transverse Mercator (UTM) coordinate system. Each UTM zone is next processed as a local area of interest that is further divided into fine-grained cells to perform the initial GPS encoding. We train a neural network in each UTM zone to learn the semantic embeddings from the initial GPS encoding. The training labels can be automatically derived from large-scale geotagged documents such as tweets, check-ins, and images that are available from social sharing platforms. We evaluate the effectiveness of our proposed GPS embeddings in geotagged image classification. Improved classification results have been obtained based on a simple early feature fusion technique.Publication Repeated intrathecal administration of plasmid DNA complexed with polyethylene glycol-grafted polyethylenimine led to prolonged transgene expression in the spinal cord(2003) Shi, L.; Tang, G.P.; Gao, S.J.; Ma, Y.X.; Liu, B.H.; Li, Y.; Zeng, J.M.; Leong, K.W.; Wang, S.; Ng, Y.K.; ANATOMY; BIOLOGICAL SCIENCESPublication Ion-exchange membrane chromatography method for rapid and efficient purification of recombinant baculovirus and baculovirus gp64 protein(2007-07) Wu, C.; Ker, Y.S.; Wang, S.; BIOLOGICAL SCIENCESSignificant progress in the application of baculoviral vectors for gene delivery into mammalian cells calls for the development of powerful methods for virus purification and concentration. We report here a novel and efficient method based on membrane chromatography to prepare baculoviral stocks. On a strong cation-exchange membrane unit, baculovirus in insect cell culture supernatants was captured at a flow rate of 3 ml/min and efficiently eluted at the same flow rate with a physiological buffer containing 150 mM NaCl as a desorption reagent. The procedure allowed for a final recovery of 78% of infective viral particles from the original supernatant and 30-fold enrichment. The high purity of the viral preparation was demonstrated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis. Baculovirus gp64 proteins could be purified by the same method, indicating the importance of the protein in mediating the binding of baculovirus to the cation-exchange membrane. The method developed should be suitable for preparing baculoviral stocks, and probably other gp64-pseudotyped viral vectors, for gene therapy applications. © Mary Ann Liebert, Inc.Publication Antigenically Modified Human Pluripotent Stem Cells Generate Antigen-Presenting Dendritic Cells(2015) Zeng, J; Wu, C; Wang, S; BIOLOGYHuman pluripotent stem cells (hPSCs) provide a promising platform to produce dendritic cell (DC) vaccine. To streamline the production process, we investigated a unique antigen-loading strategy that suits this novel platform. Specifically, we stably modified hPSCs using tumour antigen genes in the form of a full-length tumour antigen gene or an artificial tumour antigen epitope-coding minigene. Such antigenically modified hPSCs were able to differentiate into tumour antigen-presenting DCs. Without conventional antigen-loading, DCs derived from the minigene-modified hPSCs were ready to prime a tumour antigen-specific T cell response and further expand these specific T cells in restimulation processes. These expanded tumour antigen-specific T cells were potent effectors with central memory or effector memory phenotype. Thus, we demonstrated that immunocompetent tumour antigen-loaded DCs can be directly generated from antigenically modified hPSCs. Using such strategy, we can completely eliminate the conventional antigen-loading step and significantly simplify the production of DC vaccine from hPSCs.Publication Baculoviral vector-mediated transient and stable transgene expression in human embryonic stem cells(2007) Zeng, J.; Du, J.; Zhao, Y.; Palanisamy, N.; Wang, S.; BIOLOGICAL SCIENCESHuman embryonic stem (hES) cells as a renewable cell source have great prospective applications in both developmental biology research and regenerative medicine. To realize these potentials, the development of effective and safe genetic manipulation methods in hES cells is an obvious demand. We report here that baculoviral vectors were able to transduce hES cells efficiently. In transient transduction experiments, a recombinant baculoviral vector equipped with a human elongation factor 1-α promoter and a woodchuck hepatitis post-transcriptional regulatory element transduced up to 80% of cells in hES cell clumps and embryoid bodies. For prolonged transgene expression, hybrid baculoviral vectors that have incorporated a rep gene and inverted terminal repeat sequences from adeno-associated virus were produced. These hybrid vectors yielded stable transgene expression during the prolonged undifferentiated proliferation of hES cells and after differentiation. Baculoviral transduction did not affect the normal growth, phenotype, and pluripotency of hES cells. Thus, baculoviral vectors suitable for both transient overexpression and longterm stable expression are an attractive option for genetic manipulation of hES cells. ©AlphaMed Press.Publication Baculovirus: An insect-derived vector for diverse gene transfer applications(2013-04) Airenne, K.J.; Hu, Y.-C.; Kost, T.A.; Smith, R.H.; Kotin, R.M.; Ono, C.; Matsuura, Y.; Wang, S.; Ylä-Herttuala, S.; BIOLOGICAL SCIENCESInsect-derived baculoviruses have emerged as versatile and safe workhorses of biotechnology. Baculovirus expression vectors (BEVs) have been applied widely for crop and forest protection, as well as safe tools for recombinant protein production in insect cells. However, BEVs ability to efficiently transduce noninsect cells is still relatively poorly recognized despite the fact that efficient baculovirus-mediated in vitro and ex vivo gene delivery into dormant and dividing vertebrate cells of diverse origin has been described convincingly by many authors. Preliminary proof of therapeutic potential has also been established in preclinical studies. This review summarizes the advantages and current status of baculovirus-mediated gene delivery. Stem cell transduction, preclinical animal studies, tissue engineering, vaccination, cancer gene therapy, viral vector production, and drug discovery are covered. © The American Society of Gene & Cell Therapy.Publication Transmembrane protein 18 enhances the tropism of neural stem cells for glioma cells(2008-06-15) Jurvansuu, J.; Zhao, Y.; Leung, D.S.Y.; Boulaire, J.; Yuan, H.Y.; Ahmed, S.; Wang, S.; INSTITUTE OF MOLECULAR & CELL BIOLOGY; BIOLOGICAL SCIENCESThe failure of current glioma therapies is mainly due to the ability of the tumor cells to invade extensively the surrounding healthy brain tissue, hence escaping localized treatments. Neural stem cells (NSC) are able to home in on tumor foci at sites distant from the main tumor mass, possibly enabling treatment of scattered glioma clusters. To make the strategy more effective, we performed a cDNA expression library screening to identify the candidate genes that once overexpressed would enhance the tropism of NSCs for gliomas. Here, we show that a previously unannotated gene, the one encoding transmembrane protein 18 (TMEM18), is one such gene. Overexpression of TMEM18 was seen in the current study to provide NSCs and neural precursors an increased migration capacity toward glioblastoma cells in vitro and in the rat brain. Functional inactivation of the TMEM18 gene resulted in almost complete loss of the migration activity of these cells. Thus, TMEM18 is a novel cell migration modulator. Overexpression of this protein could be favorably used in NSC-based glioma therapy. ©2008 American Association for Cancer Research.