Browsing by Author "Chiou, Shih-Hwa"

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A temperature-induced and shear-reversible assembly of latanoprost-loaded amphiphilic chitosan colloids: Characterization and in vivo glaucoma treatment
(2014-07-01)
Hsiao, Meng-Hsuan
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Chiou, Shih-Hwa
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Larsson, Mikael
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Hung, Kuo-Hsuan
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Wang, Yi-Ling
Hydrogels composed of assembled colloids is a material class that is currently receiving much interest and shows great promise for use in biomedical applications. This emerging material class presents unique properties derived from the combination of nanosized domains in the form of colloidal particles with a continuous gel network and an interspersed liquid phase. Here we developed an amphiphilic chitosan based, thermogelling, shear-reversible colloidal gel system for improved glaucoma treatment and addressed how preparation procedures and loading with the anti-glaucoma drug latanoprost and commonly used preservative benzalkonium chloride influenced the mechanical properties of and drug release from the colloidal gels. The results highlight that incorporated substances and preparation procedures have effects both on mechanical properties and drug release, but that the release of drug loaded in the colloidal carriers is mainly limited by transport out of the carriers, rather than by diffusion within the gel. The developed colloidal chitosan based gels hold outstanding biomedical potential, as confirmed by the ease of preparation and administration, low cytotoxicity in MTT assay, excellent biocompatibility and lowering of intraocular pressure for 40 days in a rabbit glaucoma model. The findings clearly justify further investigations towards clinical use in the treatment of glaucoma. Furthermore, the use of this shear-reversible colloidal gel could easily be extended to localized treatment of a number of critical conditions, from chronic disorders to cancer, potentially resulting in a number of new therapeutics with improved clinical performance. (C) 2014 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.
Ash2l interacts with Oct4-stemness circuitry to promote super-enhancer-driven pluripotency network
(2019-11-04)
Tsai, Ping-Hsing
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Chien, Yueh
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Wang, Mong-Lien
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Hsu, Chih-Hung
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Laurent, Benoit
Pluripotency and cell fates can be modulated through the regulation of super-enhancers; however, the underlying mechanisms are unclear. Here, we showed a novel mechanism in which Ash2l directly binds to super-enhancers of several stemness genes to regulate pluripotency and self-renewal in pluripotent stem cells. Ash2l recruits Oct4/Sox2/Nanog (OSN) to form Ash2l/OSN complex at the super-enhancers of Jarid2, Nanog, Sox2 and Oct4, and further drives enhancer activation, upregulation of stemness genes, and maintains the pluripotent circuitry. Ash2l knockdown abrogates the OSN recruitment to all super-enhancers and further hinders the enhancer activation. In addition, CRISPRi/dCas9-mediated blocking of Ash2l-binding motifs at these super-enhancers also prevents OSN recruitment and enhancer activation, validating that Ash2l directly binds to super-enhancers and initiates the pluripotency network. Transfection of Ash2l with W118A mutation to disrupt Ash2l-Oct4 interaction fails to rescue Ash2l-driven enhancer activation and pluripotent gene upregulation in Ash2l-depleted pluripotent stem cells. Together, our data demonstrated Ash2l formed an enhancer-bound Ash2l/OSN complex that can drive enhancer activation, govern pluripotency network and stemness circuitry.
Biomedical applications and colloidal properties of amphiphilically modified chitosan hybrids
(2013-09-01)
Larsson, Mikael
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Huang, Wei-Chen
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Hsiao, Meng-Hsuan
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Wang, Yen-Jen
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Nyden, Magnus
Chitosan is among the most abundant biopolymers on earth and has been either used or exhibited potential in a wide variety of industrial and biomedical applications. With the advancement of materials technologies, chitosan has been chemically modified to self-assemble into nanoarchitectures that are usable in advanced biomedical applications, such as drug nanocarriers, macroscopic injectables, tissue-engineering scaffolds, and nanoimaging agents. Colloidal amphiphilically modified chitosan (AMC) is a relatively recent material receiving increased attention with numerous publications addressing the medical advantages of specific systems. To date, many reviews have focused on the synthesis and biomedical properties of chitosan-based biomaterials, but a comprehensive study focusing on the colloidal properties of AMC in relation to biomedical performance appears to be lacking. This review provides a survey of the field, critically reviewing the colloidal properties and biomedical performance of AMC systems, such as nanoparticle drug delivery systems and macroscopic medical devices. Finally, the future development, market potential, and clinical implications of these promising colloidal-structured biomaterials are summarised. (C) 2013 Elsevier Ltd. All rights reserved.
Carboxylated nanodiamond-mediated CRISPR-Cas9 delivery of human retinoschisis mutation into human iPSCs and mouse retina
(2020-01-01)
Yang, Tien-Chun
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Chang, Chia-Yu
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Yarmishyn, Aliaksandr A.
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Mao, Yen-Shiang
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Yang, Yi-Ping
Nanodiamonds (NDs) are considered to be relatively safe carbon nanomaterials used for the transmission of DNA, proteins and drugs. The feasibility of utilizing the NDs to deliver CRISPR-Cas9 system for gene editing has not been clearly studied. Therefore, in this study, we aimed to use NDs as the carriers of CRISPR-Cas9 components designed to introduce the mutation in RS1 gene associated with Xlinked retinoschisis (XLRS). ND particles with a diameter of 3 nm were functionalized by carboxylation of the surface and covalently conjugated with fluorescent mCherry protein. Two linear DNA constructs were attached to the conjugated mCherry: one encoded Cas9 endonuclease and GFP reporter, another encoded sgRNA and contained insert of HDR template designed to introduce RS1 c.625C>T mutation. Such nanoparticles were successfully delivered and internalized by human iPSCs and mouse retinas, the efficiency of internalization was significantly improved by mixing with BSA. The delivery of ND particles led to introduction of RS1 c.625C>T mutation in both human iPSCs and mouse retinas. Rs1 gene editing in mouse retinas resulted in several pathological features typical for XLRS, such as aberrant photoreceptor structure. To conclude, our ND-based CRISPR-Cas9 delivery system can be utilized as a tool for creating in vitro and in vivo disease models of XLRS. Statement of significance X-linked retinoschisis (XLRS) is a prevalent hereditary retinal disease, which is caused by mutations in RS1 gene, whose product is important for structural organization of the retina. The recent development of genome editing techniques such as CRISPR-Cas9 significantly improved the prospects for better understanding the pathology and development of treatment for this disease. Firstly, gene editing can allow development of appropriate in vitro and in vivo disease models; secondly, CRISPR-Cas9 can be applied for gene therapy by removing the disease-causative mutation in vivo. The major prerequisite for these approaches is to develop safe and efficient CRISPR-Cas9 delivery system. In this study, we tested specifically modified nanodiamonds for such a delivery system. We were able to introduce Rs1 mutation into the mouse retina and, importantly, observed several XLRS-specific effects. (C) 2019 Acta Materialia Inc. Published by Elsevier Ltd.
Cisplatin-selected resistance is associated with increased motility and stem-like properties via activation of STAT3/Snail axis in atypical teratoid/rhabdoid tumor cells
(2015-01-30)
Liu, Wei-Hsiu
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Chen, Ming-Teh
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Wang, Mong-Lien
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Lee, Yi-Yen
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Chiou, Guang-Yuh
Atypical teratoid/rhabdoid tumor (ATRT) is a malignant pediatric brain tumor with great recurrence after complete surgery and chemotherapy. Here, we demonstrate that cisplatin treatment selects not only for resistance but also for a more oncogenic phenotype characterized by high self-renewal and invasive capabilities. These phenomena are likely due to STAT3 upregulatoin which occurred simultaneously with higher expression of Snail, an activator of epithelial-mesenchymal transition (EMT), in ATRT-CisR cells. STAT3 knockdown effectively suppressed Snail expression and blocked motility and invasion in ATRT-CisR cells, while overexpressing Snail reversed these effects. Chromatin immunoprecipitation assay indicated that STAT3 directly bound to Snail promoter. Moreover, STAT3 knockdown effectively suppressed cancer stem-like properties, synergistically enhanced the chemotherapeutic effect, and significantly improved survival rate in ATRT-CisR-transplanted immunocompromised mice. Finally, immunohistochemistrical analysis showed that STAT3 and Snail were coexpressed at high levels in recurrent ATRT tissues. Thus, the STAT3/Snail pathway plays an important role in oncogenic resistance, rendering cells not only drug-resistant but also increasingly oncogenic (invasion, EMT and recurrence). Therefore, the STAT3/Snail could be a target for ATRT treatment.
Corneal repair by human corneal keratocyte-reprogrammed iPSCs and amphiphatic carboxymethyl-hexanoyl chitosan hydrogel
(2012-11-01)
Chien, Yueh
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Liao, Yi-Wen
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Liu, Dean-Mo
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Lin, Heng-Liang
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Chen, Shih-Jen
Induced pluripotent stem cells (iPSCs) have promising potential in regenerative medicine, but whether iPSCs can promote corneal reconstruction remains undetermined. In this study, we successfully reprogrammed human corneal keratocytes into iPSCs. To prevent feeder cell contamination, these iPSCs were cultured onto a serum- and feeder-free system in which they remained stable through 30 passages and showed ESC-like pluripotent property. To investigate the availability of iPSCs as bioengineered substitutes in corneal repair, we developed a thermo-gelling injectable amphiphatic carboxymethyl-hexanoyl chitosan (CHC) nanoscale hydrogel and found that such gel increased the viability and CD44 + proportion of iPSCs, and maintained their stem-cell like gene expression, in the presence of culture media. Combined treatment of iPSC with CHC hydrogel (iPSC/CHC hydrogel) facilitated wound healing in surgical abrasion-injured corneas. In severe corneal damage induced by alkaline, iPSC/CHC hydrogel enhanced corneal reconstruction by downregulating oxidative stress and recruiting endogenous epithelial cells to restore corneal epithelial thickness. Therefore, we demonstrated that these human keratocyte-reprogrammed iPSCs, when combined with CHC hydrogel, can be used as a rapid delivery system to efficiently enhance corneal wound healing. In addition, iPSCs reprogrammed from corneal surgical residues may serve as an alternative cell source for personalized therapies for human corneal damage. (C) 2012 Elsevier Ltd. All rights reserved.
Deep learning assisted detection of glaucomatous optic neuropathy and potential designs for a generalizable model
(2020-05-14)
Ko, Yu-Chieh
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Wey, Shih-Yu
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Chen, Wei-Ta
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Chang, Yu-Fan
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Chen, Mei-Ju
Purpose To evaluate ways to improve the generalizability of a deep learning algorithm for identifying glaucomatous optic neuropathy (GON) using a limited number of fundus photographs, as well as the key features being used for classification. Methods A total of 944 fundus images from Taipei Veterans General Hospital (TVGH) were retrospectively collected. Clinical and demographic characteristics, including structural and functional measurements of the images with GON, were recorded. Transfer learning based on VGGNet was used to construct a convolutional neural network (CNN) to identify GON. To avoid missing cases with advanced GON, an ensemble model was adopted in which a support vector machine classifier would make final classification based on cup-to-disc ratio if the CNN classifier had low-confidence score. The CNN classifier was first established using TVGH dataset, and then fine-tuned by combining the training images of TVGH and DrishtiGS datasets. Class activation map (CAM) was used to identify key features used for CNN classification. Performance of each classifier was determined through area under receiver operating characteristic curve (AUC) and compared with the ensemble model by diagnostic accuracy. Results In 187 TVGH test images, the accuracy, sensitivity, and specificity of the CNN classifier were 95.0%, 95.7%, and 94.2%, respectively, and the AUC was 0.992 compared to the 92.8% accuracy rate of the ensemble model. For the Drishti-GS test images, the accuracy of the CNN, the fine-tuned CNN and ensemble model was 33.3%, 80.3%, and 80.3%, respectively. The CNN classifier did not misclassify images with moderate to severe diseases. Class-discriminative regions revealed by CAM co-localized with known characteristics of GON. Conclusions The ensemble model or a fine-tuned CNN classifier may be potential designs to build a generalizable deep learning model for glaucoma detection when large image databases are not available.
Demethoxycurcumin-Carrying Chitosan Antibody Core Shell Nanoparticles with Multitherapeutic Efficacy toward Malignant A549 Lung Tumor: From in Vitro Characterization to in Vivo Evaluation
(2015-04-01)
Huang, Wei-Ting
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Larsson, Mikael
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Wang, Yen-Jen
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Chiou, Shih-Hwa
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Lin, Hui-Yi
Targeting controlled release core-shell nanocarriers with the potential to overcome multidrug resistant (MDR) lung cancer were prepared based on demethoxycurcumin (DMC) loaded amphiphilic chitosan nanoparticles coated with an anti-EGFR antibody layer. The nanocarriers were characterized with regard to size with dynamic light scattering, SEM, and TEM. The characterization confirmed the nanocarriers to have a surface coating of the anti-EGFR antibody and a final size excellently suited for circulating targeting nanocarriers, i.e., <200 nm in diameter. In vitro drug release revealed extended quasi-Fickian release from the nanocarriers, with the anti-EGFR layer further reducing the release rate. Cell culture experiments using normoxic and MDR hypoxic cells overexpressing EGFR confirmed improved DMC delivery for anti-EGFR coated particles and revealed that the DMC was delivered to the cytoplasmic region of the cells, forming nanoprecipitates in lysosomes and endosomes. The effective endocytosis and targeting of the core-shell nanoparticles resulted in the nanocarriers achieving high cytotoxicity also against MDR cells. The therapeutic potential was further confirmed in an A549 xenograft lung tumor mouse model, where DMC loaded core-shell nanocarriers achieved about 8-fold reduction in tumor volume compared with control group over the 8 weeks of the investigation. Both in vitro and in vivo data suggest the anti-EGFR coated core-shell nanocarriers as highly promising for treatment of hypoxic MDR cancers, especially for non-small cell lung cancer.
Enhanced Antioxidant Capacity of Dental Pulp-Derived iPSC-Differentiated Hepatocytes and Liver Regeneration by Injectable HGF-Releasing Hydrogel in Fulminant Hepatic Failure
(2015-01-01)
Chiang, Chih-Hung
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Wu, Wai-Wah
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Li, Hsin-Yang
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Chien, Yueh
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Sun, Cho-Chin
Acute hepatic failure (AHF) is a severe liver injury leading to sustained damage and complications. Induced pluripotent stem cells (iPSCs) may be an alternative option for the treatment of AHF. In this study, we reprogrammed human dental pulp-derived fibroblasts into iPSCs, which exhibited pluripotency and the capacity to differentiate into tridermal lineages, including hepatocyte-like cells (iPSC-Heps). These iPSC-Heps resembled human embryonic stem cell-derived hepatocyte-like cells in gene signature and hepatic markers/functions. To improve iPSC-Heps engraftment, we next developed an injectable carboxymethyl-hexanoyl chitosan hydrogel (CHC) with sustained hepatocyte growth factor (HGF) release (HGF CHC) and investigated the hepatoprotective activity of HGF CHC-delivered iPSC-Heps in vitro and in an immunocompromised AHF mouse model induced by thioacetamide (TAA). Intrahepatic delivery of HGF CHC iPSC-Heps reduced the TAA-induced hepatic necrotic area and rescued liver function and recipient viability. Compared with PBS-delivered iPSC-Heps, the HGF CHC-delivered iPSC-Heps exhibited higher antioxidant and antiapoptotic activities that reduced hepatic necrotic area. Importantly, these HGF CHC-mediated responses could be abolished by administering anti-HGF neutralizing antibodies. In conclusion, our findings demonstrated that HGF mediated the enhancement of iPSC-Hep antioxidant/antiapoptotic capacities and hepatoprotection and that HGF CHC is as an excellent vehicle for iPSC-Hep engraftment in iPSC-based therapy against AHF.
Epigenetic Regulation of the miR142-3p/Interleukin-6 Circuit in Glioblastoma
(2013-12-12)
Chiou, Guang-Yuh
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Chien, Chian-Shiu
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Wang, Mong-Lien
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Chen, Ming-Teh
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Yang, Yi-Ping
Epigenetic regulation plays a critical role in glioblastoma (GBM) tumorigenesis. However, how microRNAs (miRNAs) and cytokines cooperate to regulate GBM tumor progression is still unclear. Here, we show that interleukin-6 (IL-6) inhibits miR142-3p expression and promotes GBM propagation by inducing DNA methyltransferase 1-mediated hypermethylation of the miR142-3p promoter. Interestingly, miR142-3p also suppresses IL-6 secretion by targeting the 3' UTR of IL-6. In addition, miR142-3p also targets the 3' UTR and suppresses the expression of high-mobility group AT-hook 2 (HMGA2), leading to inhibition of Sox2-related sternness. We further show that HMGA2 enhances Sox2 expression by directly binding to the Sox2 promoter. Clinically, GBM patients whose tumors present upregulated IL-6, HMGA2, and Sox2 protein expressions and hypermethylated miR142-3p promoter also demonstrate poor survival outcome. Orthotopic delivery of miR142-3p blocks IL-6/HMGA2/Sox2 expression and suppresses stem-like properties in GBM-xenotransplanted mice. Collectively, we discovered an IL-6/miR142-3p feed-back-loop-dependent regulation of GBM malignancy that could be a potential therapeutic target.
Glutamate Stimulation Dysregulates AMPA Receptors-Induced Signal Transduction Pathway in Leber's Inherited Optic Neuropathy Patient-Specific hiPSC-Derived Retinal Ganglion Cells
(2019-06-01)
Yang, Yi-Ping
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Phan Nguyen Nhi Nguyen
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Lin, Tai-Chi
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Yarmishyn, Aliaksandr A.
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Chen, Wun-Syuan
The mitochondrial genetic disorder, Leber's hereditary optic neuropathy (LHON), is caused by a mutation in MT-ND4 gene, encoding NADH dehydrogenase subunit 4. It leads to the progressive death of retinal ganglion cells (RGCs) and causes visual impairment or even blindness. However, the precise mechanisms of LHON disease penetrance and progression are not completely elucidated. Human-induced pluripotent stem cells (hiPSCs) offer unique opportunities to investigate disease-relevant phenotypes and regulatory mechanisms underlying LHON pathogenesis at the cellular level. In this study, we successfully generated RGCs by differentiation of LHON patient-specific hiPSCs. We modified the protocol of differentiation to obtain a more enriched population of single-cell RGCs for LHON study. Based on assessing morphology, expression of specific markers and electrophysiological activity, we found that LHON-specific hiPSC-derived were more defective in comparison with normal wild-type RGCs. Based on our previous study, whereby by using microarray analysis we identified that the components of glutamatergic synapse signaling pathway were significantly downregulated in LHON-specific RGCs, we focused our study on glutamate-associated alpha -amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors. We found that the protein expression levels of the subunits of the AMPA receptor, GluR1 and GluR2, and their associated scaffold proteins were decreased in LHON-RGCs. By performing the co-immunoprecipitation assay, we found several differences in the efficiencies of interaction between AMPA subunits and scaffold proteins between normal and LHON-specific RGCs.
Imbalanced Production of Reactive Oxygen Species and Mitochondrial Antioxidant SOD2 in Fabry Disease-Specific Human Induced Pluripotent Stem Cell-Differentiated Vascular Endothelial Cells
(2017-01-01)
Tseng, Wei-Lien
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Chou, Shih-Jie
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Chiang, Huai-Chih
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Wang, Mong-Lien
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Chien, Chian-Shiu
Fabry disease (FD) is an X-linked inherited lysosomal storage disease caused by alpha-galactosidase A (GLA) deficiency. Progressive intracellular accumulation of globotriaosylceramide (Gb3) is considered to be pathogenically responsible for the phenotype variability of FD that causes cardiovascular dysfunction; however, molecular mechanisms underlying the impairment of FD-associated cardiovascular tissues remain unclear. In this study, we reprogrammed human induced pluripotent stem cells (hiPSCs) from peripheral blood cells of patients with FD (FD-iPSCs); subsequently differentiated them into vascular endothelial-likecells (FD-ECs) expressing CD31, VE-cadherin, and vWF; and investigated their ability to form vascular tube-like structures. FD-ECs recapitulated the FD pathophysiological phenotype exhibiting intracellular Gb3 accumulation under a transmission electron microscope. Moreover, compared with healthy control iPSC-derived endothelial cells (NC-ECs), reactive oxygen species (ROS) production considerably increased in FD-ECs. Microarray analysis was performed to explore the possible mechanism underlying Gb3 accumulation-induced ROS production in FD-ECs. Our results revealed that superoxide dismutase 2 (SOD2), a mitochondrial antioxidant, was significantly downregulated in FD-ECs. Compared with NC-ECs, AMPK activity was significantly enhanced in FD-ECs. Furthermore, to investigate the role of Gb3 in these effects, human umbilical vein endothelial cells (HUVECs) were treated with Gb3. After Gb3 treatment, we observed that SOD2 expression was suppressed and AMPK activity was enhanced in a dose-dependent manner. Collectively, our results indicate that excess accumulation of Gb3 suppressed SOD2 expression, increased ROS production, enhanced AMPK activation, and finally caused vascular endothelial dysfunction. Our findings suggest that dysregulated mitochondrial ROS may be a potential target for treating FD.
Laminin modification subretinal bio-scaffold remodels retinal pigment epithelium-driven microenvironment in vitro and in vivo
(2016-10-04)
Peng, Chi-Hsien
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Chuang, Jen-Hua
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Wang, Mong-Lien
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Jhan, Yong-Yu
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Chien, Ke-Hung
Advanced age-related macular degeneration (AMD) may lead to geographic atrophy or fibrovascular scar at macular, dysfunctional retinal microenvironment, and cause profound visual loss. Recent clinical trials have implied the potential application of pluripotent cell-differentiated retinal pigment epithelial cells (dRPEs) and membranous scaffolds implantation in repairing the degenerated retina in AMD. However, the efficacy of implanted membrane in immobilization and supporting the viability and functions of dRPEs, as well as maintaining the retinal microenvironment is still unclear. Herein we generated a biomimetic scaffold mimicking subretinal Bruch\'s basement from plasma modified polydimethylsiloxane (PDMS) sheet with laminin coating (PDMS-PmL), and investigated its potential functions to provide a subretinal environment for dRPE-monolayer grown on it. Firstly, compared to non-modified PDMS, PDMS-PmL enhanced the attachment, proliferation, polarization, and maturation of dRPEs. Second, PDMS-PmL increased the polarized tight junction, PEDF secretion, melanosome pigment deposit, and phagocytotic-ability of dRPEs. Third, PDMS-PmL was able to carry a dRPEs/ photoreceptor-precursors multilayer retina tissue. Finally, the in vivo subretinal implantation of PDMS-PmL in porcine eyes showed well-biocompatibility up to 2-year follow-up. Notably, multifocal ERGs at 2-year follow-up revealed well preservation of macular function in PDMS-PmL, but not PDMS, transplanted porcine eyes. Trophic PEDF secretion of macular retina in PDMS-PmL group was also maintained to preserve retinal microenvironment in PDMS-PmL eyes at 2 year. Taken together, these data indicated that PDMS-PmL is able to sustain the physiological morphology and functions of polarized RPE monolayer, suggesting its potential of rescuing macular degeneration in vivo.
Morphological and Molecular Defects in Human Three-Dimensional Retinal Organoid Model of X-Linked Juvenile Retinoschisis
(2019-11-12)
Huang, Kang-Chieh
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Wang, Mong-Lien
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Chen, Shih-Jen
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Kuo, Jean-Cheng
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Wang, Won-Jing
X-linked juvenile retinoschisis (XLRS), linked to mutations in the RS1 gene, is a degenerative retinopathy with a retinal splitting phenotype. We generated human induced pluripotent stem cells (hiPSCs) from patients to study XLRS in a 3D retinal organoid in vitro differentiation system. This model recapitulates key features of XLRS including retinal splitting, defective retinoschisin production, outer-segment defects, abnormal paxillin turnover, and impaired ER-Golgi transportation. RS1 mutation also affects the development of photoreceptor sensory cilia and results in altered expression of other retinopathy-associated genes. CRISPR/Cas9 correction of the disease-associated C625T mutation normalizes the splitting phenotype, outer-segment defects, paxillin dynamics, ciliary marker expression, and transcriptome profiles. Likewise, mutating RS1 in control hiPSCs produces the disease-associated phenotypes. Finally, we show that the C625T mutation can be repaired precisely and efficiently using a base-editing approach. Taken together, our data establish 3D organoids as a valid disease model.
Musashi-1 Enhances Glioblastoma Cell Migration and Cytoskeletal Dynamics through Translational Inhibition of Tensin3
(2017-08-18)
Chen, Hsiao-Yun
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Lin, Liang-Ting
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Wang, Mong-Lien
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Laurent, Benoit
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Hsu, Chih-Hung
The RNA-binding protein Musashi-1 (MSI1) exerts essential roles in multiple cellular functions, such as maintenance of self-renewal and pluripotency of stem cells. MSI1 overexpression has been observed in several tumor tissues, including glioblastoma (GBM), and is considered as a well-established marker for tumor metastasis and recurrence. However, the molecular mechanisms by which MSI1 regulates cell migration are still undetermined. Here we reported that MSI1 alters cell morphology, promotes cell migration, and increases viscoelasticity of GBM cells. We also found that MSI1 directly binds to the 3'UTR of Tensin 3 (TNS3) mRNA, a negative regulator of cell migration, to inhibit its translation. Additionally, we identified that RhoA-GTP could be a potential regulator in MSI1/TNS3-mediated cell migration and morphological changes. In a xenograft animal model, high expression ratio of MSI1 to TNS3 enhanced GBM tumor migration. We also confirmed that MSI1 and TNS3 expressions are mutually exclusive in migratory tumor lesions, and GBM patients with MSI1(high)/TNS3(low) pattern tend to have poor clinical outcome. Taken together, our findings suggested a critical role of MSI1-TNS3 axis in regulating GBM migration and highlighted that the ratio of MSI1/TNS3 could predict metastatic and survival outcome of GBM patients.
Printable Graphene Oxide Micropatterns for a Bio-Subretinal Chip
(2018-09-19)
Yang, Jia-Wei
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Tseng, Ming-Liang
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Fu, Yu-Min
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Kang, Che-Hao
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Cheng, Yu-Ting
Recently, implantable artificial subretinal chips using electronic components have replaced photoreceptors to serve as the most feasible treatment for retinal diseases. As such a chip that is meant to be implanted and used for very long periods, growing retinal cells on it to improve the electrical stimulation efficiency and attraction of neuronal elements remains a challenge. Here, an inkjet printing technology is employed to create graphene oxide (GO) micropatterns onto microelectrodes of a photovoltaic-powered implantable retinal chip. These GO micropatterns allow human retinal pigment epithelium (RPE) cells to specially attach and grow in each microelectrode. In addition, the cell proliferation, viability, and tight junction of RPE cells are improved during culturing. The development of a simple surface-coating technology would pave the way for the development of the first fully integrated and encapsulated retinal prostheses with biocompatible on-chip microelectrodes for long-term implantation, which could be effectively applied in retina tissue engineering and therapy.
Supercontinuum source-based multi-contrast optical coherence tomography for rat retina imaging
(2018-12-01)
Syu, Jia-Pu
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Buddhakosai, Waradee
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Chen, Shih-Jen
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Ke, Chang-Chih
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Chiou, Shih-Hwa
This study proposed an ultrahigh-resolution multi-contrast optical coherence tomography system integrated with fundus photography for in vivo retinal imaging of rodents. A supercontinuum light source was used in the system, providing an axial resolution of less than 3 mu m within 1.8 mm (in the tissue). Three types of tissue contrast based on backscattered intensity, phase retardation, and microvasculature at a capillary level can be simultaneously obtained using the proposed system. Pigmented Long-Evans, non-pigmented (albino) Sprague Dawley, and Royal College of Surgeons rats were imaged and compared. In vivo imaging results were validated with histology. (C) 2018 Optical Society of America under the terms of the OSA Open Access Publishing Agreement
The use of polymer-based nanoparticles and nanostructured materials in treatment and diagnosis of cardiovascular diseases: Recent advances and emerging designs
(2016-06)
Wang, Yen-Jen
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Larsson, Mikael
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Huang, Wei-Ting
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Chiou, Shih-Hwa
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Nicholls, Stephen J.
This review summarizes important advances in polymer-based nanotechnologies for the treatment and diagnosis of cardiovascular diseases, focusing on nanoparticles and nanostructured materials/devices. The current state of the art and design parameters are discussed with the aim of providing a source of information that can aid in the development of new treatments by bridging between materials development, preclinical, and clinical trials. This is highly relevant as cardiovascular diseases remain a leading cause of death worldwide and as current treatments burden the healthcare systems with great costs. Different strategies, from targeting theranostic nanocarriers, to dual-drug depot systems, injectable cell scaffolds, and LDL acceptors are treated. The review ends with a concluding outlook on the ossibilities and challenges presented to polymer-based nanotechnologies in cardiovascular disease therapy. (c) 2016 Elsevier Ltd. All rights reserved.