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Gu H.,Nanyang Technological University | Yue Z.,Institute of Biotechnology and Nanotechnology | Leong W.S.,Nanyang Technological University | Nugraha B.,Institute of Biotechnology and Nanotechnology | And 2 more authors.
Regenerative Medicine | Year: 2010

Background: Mesenchymal stem cells (MSCs) are multipotent cells that can be induced to differentiate into multiple cell lineages, including neural cells. They are a good cell source for neural tissue-engineering applications. Cultivation of human (h)MSCs in 3D scaffolds is an effective means for the development of novel neural tissue-engineered constructs, and may serve as a promising strategy in the treatment of nerve injury. Aim: This study presents the in vitro growth and neural differentiation of hMSCs in 3D macroporous, cellulosic hydrogels. Results: The number of hMSCs cultivated in the 3D scaffolds increased by more than 14-fold after 7 days. After 2 days induction, most of the hMSCs in the 3D scaffolds were positive for nestin, a marker of neural stem cells. After 7 days induction, most of the hMSCs in the 3D scaffolds showed glial fibrillary acidic protein, tubulin or neurofilament M-positive reaction and a few hMSCs were positive for nestin. After 14 days induction, hMSCs in the 3D scaffolds could completely differentiate into neurons and glial cells. The neural differentiation of hMSCs in the 3D scaffolds was further demonstrated by real-time PCR. Conclusion: These results show that the 3D macroporous cellulosic hydrogel could be an appropriate substrate for neural differentiation of hMSCs and its possible applications in neural tissue engineering are discussed. © 2010 Future Medicine Ltd.

"Our technique detects two essential processes of embryonic development: cellular differentiation and migration," says Hanry Yu, who led the research together with his colleagues at the A*STAR Institute of Biotechnology and Nanotechnology. "This greatly enhances our ability to predict drug-induced toxicity during development." Drugs found to cause birth defects are categorized as teratogens. These include the sedative, thalidomide, initially prescribed to pregnant women to combat morning sickness until it was found to disrupt limb formation in growing fetuses. Researchers have typically tested the teratogenic effects of various compounds on animals, which is expensive, time-consuming and contested on ethical grounds. The main alternative looks at how these compounds disrupt the differentiation of mouse embryonic stem cells into beating heart muscle cells, often with unreliable results. Yu's team instead developed a drug screening model using human pluripotent stem cells that differentiate into circular structures resembling the earliest cellular layers formed during embryogenesis. The model could be used to observe teratogenic changes over time, and more significantly, space. In cell culture experiments, the researchers found that colonies treated with thalidomide tended to migrate closer to the center of the ring, whereas those treated with non teratogenic penicillin G migrated outward to form thin rings similar to those produced by untreated cells (see image). "Anyone studying embryonic biology will know that drugs that affect cellular migration in the embryo cause defects: the heart will be in the wrong place or the brain will be in the wrong place or no such organs will grow at all," says Yu. "But nobody was paying attention to this migratory pattern in drug testing." The researchers compared the performance of their cells against mouse cardiomyocytes in classifying four known teratogens and one non teratogen. The mouse model misclassified two of the five drugs, including thalidomide, which only affects human and not mouse development. Yu's model, however, identified all five drugs correctly. The researchers have since tested their model on 11 other drugs, with close to 100 per cent predictability of teratogenicity, and plan to test another 30 with funding from A*STAR's technology transfer arm, ETPL (Exploit Technologies Pte Ltd). "Once we reach 50 or more compounds, the community will be convinced," says Yu, describing a pharmaceutical industry eager to cut its losses on drugs found to be harmful to health. Explore further: Full-length Chd1 protein is needed for embryonic stem cell differentiation More information: Jiangwa Xing et al. A method for human teratogen detection by geometrically confined cell differentiation and migration, Scientific Reports (2015). DOI: 10.1038/srep10038

Yin L.,Alliance Technology Group | Xu S.,Nanyang Technological University | Cheng J.,Nanyang Technological University | Zheng D.,Alliance Technology Group | And 12 more authors.
Journal of Biomedical Optics | Year: 2013

Lung injury caused by influenza virus infection is widespread. Understanding lung damage and repair progression post infection requires quantitative spatiotemporal information on various cell types mapping into the tissue structure. Based on high content images acquired from an automatic slide scanner, we have developed algorithms to quantify cell infiltration in the lung, loss and recovery of Clara cells in the damaged bronchioles and alveolar type II cells (AT2s) in the damaged alveolar areas, and induction of pro-surfactant protein C (pro-SPC)-expressing bronchiolar epithelial cells (SBECs). These quantitative analyses reveal: prolonged immune cell infiltration into the lung that persisted long after the influenza virus was cleared and paralleled with Clara cell recovery; more rapid loss and recovery of Clara cells as compared to AT2s; and two stages of SBECs from Scgb1a1\+ to Scgb1a1-. These results provide evidence supporting a new mechanism of alveolar repair where Clara cells give rise to AT2s through the SBEC intermediates and shed light on the understanding of the lung damage and repair process. The approach and algorithms in quantifying cell-level changes in the tissue context (cell-based tissue informatics) to gain mechanistic insights into the damage and repair process can be expanded and adapted in studying other disease models. © 2013 The Authors.

Zhou J.,National University of Singapore | Bi C.,National University of Singapore | Chng W.-J.,National University of Singapore | Chng W.-J.,National University Hospital Singapore | And 13 more authors.
PLoS ONE | Year: 2011

Combination with other small molecule drugs represents a promising strategy to improve therapeutic efficacy of FLT3 inhibitors in the clinic. We demonstrated that combining ABT-869, a FLT3 inhibitor, with SAHA, a HDAC inhibitor, led to synergistic killing of the AML cells with FLT3 mutations and suppression of colony formation. We identified a core gene signature that is uniquely induced by the combination treatment in 2 different leukemia cell lines. Among these, we showed that downregulation of PTP4A3 (PRL-3) played a role in this synergism. PRL-3 is downstream of FLT3 signaling and ectopic expression of PRL-3 conferred therapeutic resistance through upregulation of STAT (signal transducers and activators of transcription) pathway activity and anti-apoptotic Mcl-1 protein. PRL-3 interacts with HDAC4 and SAHA downregulates PRL-3 via a proteasome dependent pathway. In addition, PRL-3 protein was identified in 47% of AML cases, but was absent in myeloid cells in normal bone marrows. Our results suggest such combination therapies may significantly improve the therapeutic efficacy of FLT3 inhibitors. PRL-3 plays a potential pathological role in AML and it might be a useful therapeutic target in AML, and warrant clinical investigation. © 2011 Zhou et al.

Yue Z.,Institute of Biotechnology and Nanotechnology | Wen F.,Institute of Biotechnology and Nanotechnology | Gao S.,Institute of Biotechnology and Nanotechnology | Ang M.Y.,Institute of Biotechnology and Nanotechnology | And 5 more authors.
Biomaterials | Year: 2010

This work exploits the thermal responsive phase behavior of hydroxypropylcellulose to produce 3D interconnected macroporous hydrogels in aqueous environment. Hydroxypropylcellulose was modified with allyl isocyanate, and their temperature mediated phase behavior was studied as a function of degree of modification (DS). A derivative with a DS of 1.5 was selected for scaffold preparation. Its aqueous solutions were warmed up to trigger the formation of biphasic systems. Such state was then immobilized efficiently by γ-ray irradiated crosslinking. Lyophilization of the crosslinked hydrogels yielded 3D macroporous sponges. The re-hydrated gels demonstrate a combination of interconnected macroporosity, high water content and mechanical integrity to soft tissues. Cytocompatibility was demonstrated among various cell types, and in vivo biocompatibility test showed minimal inflammatory response within 12 weeks' subcutaneous implantation in mice. The potential applications of these macroporous hydrogels in tissue engineering are discussed. © 2010 Elsevier Ltd.

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