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Establishment of advanced multi-organoid model based on functional characteristics
Bokyeong Ryu,Jin Kim,Seul-Gi Lee,Jieun Baek,C-Yoon Kim 한국실험동물학회 2021 한국실험동물학회 학술발표대회 논문집 Vol.2021 No.7
Safety/efficacy research is an important area in the drug development process, and drug screening is an essential part of this endeavor. Stem cells are the optimal tools to simulate the human system, and are continuing various developments from 2D culture to 3D organoids. The latest organoids go beyond simple phenotypic differentiation, and feature the maturation of functional mimicry due to spontaneous structural formation, which is drawing attention in the field of research. For the development of functional organoids, this study aims to develop a multi-organoid model in which the heart, blood vessels, and brain are organically connected to each other to maximize their functions. Compared with the existing single organoids, functionally mature multi-organoids exhibit structurally similar characteristics to human organs through actual blood vessel distribution. These functional organoids will have significant implications in future drug development.
Jin Kim,Bokyeong Ryu,Seul-Gi Lee,Jieun Baek,Jae-Hak Park,C-Yoon Kim 한국실험동물학회 2021 한국실험동물학회 학술발표대회 논문집 Vol.2021 No.7
Rett syndrome (RTT) is a second leading cause of mental retardation in girls affecting 1 in 10,000 female births. Loss-of-function mutations in the methyl CpG-binding protein 2 gene (MeCP2) is the cause of more than 95% of RTT cases. We hypothesized a molecular target involved in RTT: the downregulated A2A receptor, which leads to Brain-derived neurotrophic factor (BDNF) signal decrease. CGS21680, a specific agonist of A2A receptor, is a potential therapeutic drug which able to alleviate the disease phenotypes in brain disorders. We established induced pluripotent stem cells from human RTT fibroblast (T158M mutation) and differentiated into cortical neurons. Using multi-electrode array, neuron activity was compared, depending on the treatment of CGS21680 (mean firing rate and mean network burst rate). In MeCP2-R106W-Tavi mice model, CGS21680 was injected intraperitoneally from 3 weeks of age to 6 weeks. After the injection period, mice had open field test and rotarod test and showed improvements in reducing anxiety level (significant differences in total distance and mean velocity) and increasing motor activity (significant differences in latency to fall). Altogether, our findings indicate that CGS21680 is a potential drug candidate for the treatment of RTT caused by MeCP2 point mutation.
Kim, Jin,Oh, Hanseul,Ryu, Bokyeong,Kim, Ukjin,Lee, Ji Min,Jung, Cho-Rok,Kim, C-yoon,Park, Jae-Hak Elsevier 2018 Environmental pollution Vol.236 No.-
<P><B>Abstract</B></P> <P>Triclosan (TCS) is an organic compound with a wide range of antibiotic activity and has been widely used in items ranging from hygiene products to cosmetics; however, recent studies suggest that it has several adverse effects. In particular, TCS can be passed to both fetus and infants, and while some evidence suggests <I>in vitro</I> neurotoxicity, there are currently few studies concerning the mechanisms of TCS-induced developmental neurotoxicity. Therefore, this study aimed to clarify the effect of TCS on neural development using zebrafish models, by analyzing the morphological changes, the alterations observed in fluorescence using HuC-GFP and Olig2-dsRED transgenic zebrafish models, and neurodevelopmental gene expression. TCS exposure decreased the body length, head size, and eye size in a concentration-dependent manner in zebrafish embryos. It increased apoptosis in the central nervous system (CNS) and particularly affected the structure of the CNS, resulting in decreased synaptic density and shortened axon length. In addition, it significantly up-regulated the expression of genes related to axon extension and synapse formation such as <I>α1-Tubulin</I> and <I>Gap43</I>, while decreasing <I>Gfap</I> and <I>Mbp</I> related to axon guidance, myelination and maintenance. Collectively, these changes indicate that exposure to TCS during neurodevelopment, especially during axonogenesis, is toxic. This is the first study to demonstrate the toxicity of TCS during neurogenesis, and suggests a possible mechanism underlying the neurotoxic effects of TCS in developing vertebrates.</P> <P><B>Highlights</B></P> <P> <UL> <LI> TCS changes craniofacial morphology and neural structures in zebrafish embryos. </LI> <LI> TCS affects the expression of apoptosis and neurogenesis related genes. </LI> <LI> TCS is toxic to neurodevelopmental stages, especially in axonogenesis. </LI> <LI> This is the first study to confirm the developmental neurotoxicity of TCS. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>
Kim, Jin,Kim, C-yoon,Oh, Hanseul,Ryu, Bokyeong,Kim, Ukjin,Lee, Ji Min,Jung, Cho-Rok,Park, Jae-Hak Elsevier 2019 The Science of the total environment Vol.653 No.-
<P><B>Abstract</B></P> <P>Trimethyltin chloride (TMT), one of the most widely used organotin compounds in industrial and agricultural fields, is widespread in soil, aquatic systems, foodstuffs and household items. TMT reportedly has toxic effects on the nervous system; however, there is limited information about its effects on eye development and no clear associated mechanisms have been identified. Therefore, in the present study, we investigated eye morphology, vison-related behavior, reactive oxygen species (ROS) production, apoptosis, histopathology, and gene expression to evaluate the toxicity of TMT during ocular development in zebrafish embryos. Exposure to TMT decreased the axial length and surface area of the eye and impaired the ability of zebrafish to recognize light. 2′,7′-dichlorofluorescein diacetate and acridine orange assays revealed dose-dependent increases in ROS formation and apoptosis in the eye. Furthermore, pyknosis of retinal cells was confirmed through histopathological analysis. Antioxidative enzyme-related genes were downregulated and apoptosis-inducing genes were upregulated in TMT-treated zebrafish compared to expression in controls. Retinal cell-specific gene expression was suppressed mainly in retinal ganglion cells, bipolar cells, and photoreceptor cells, whereas amacrine cell-, horizontal cell-, and Müller cell-specific gene expression was enhanced. Our results demonstrate for the first time the toxicity of TMT during eye development, which occurs through the induction of ROS-mediated apoptosis in retinal cells during ocular formation.</P> <P><B>Highlights</B></P> <P> <UL> <LI> TMT causes microphthalmia and impairs visual function in zebrafish embryo. </LI> <LI> TMT induces dose-dependent increases in ROS formation and apoptosis in the eye. </LI> <LI> TMT is toxic to specific retinal cells and leads histopathological abnormalities. </LI> <LI> TMT affected the expression of genes related to above changes. </LI> <LI> This is the first study to confirm the ocular developmental toxicity of TMT. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>