Preclinical Analysis of Fetal Human Mesencephalic Neural Progenitor Cell Lines: Characterization and Safety In Vitro and In Vivo

Moon, Jisook,Schwarz, Sigrid C.,Lee, Hyun‐,Seob,Kang, Jun Mo,Lee, Young‐,Eun,Kim, Bona,Sung, Mi‐,Young,Hö,glinger, Gü,nter,Wegner, Florian,Kim, Jin Su,Chung, Hyung‐,Min unknown 2017 Stem cells translational medicine Vol.6 No.2

<P><B>Abstract</B></P><P>We have developed a good manufacturing practice for long‐term cultivation of fetal human midbrain‐derived neural progenitor cells. The generation of human dopaminergic neurons may serve as a tool of either restorative cell therapies or cellular models, particularly as a reference for phenotyping region‐specific human neural stem cell lines such as human embryonic stem cells and human inducible pluripotent stem cells. We cultivated 3 different midbrain neural progenitor lines at 10, 12, and 14 weeks of gestation for more than a year and characterized them in great detail, as well as in comparison with Lund mesencephalic cells. The whole cultivation process of tissue preparation, cultivation, and cryopreservation was developed using strict serum‐free conditions and standardized operating protocols under clean‐room conditions. Long‐term‐cultivated midbrain‐derived neural progenitor cells retained stemness, midbrain fate specificity, and floorplate markers. The potential to differentiate into authentic A9‐specific dopaminergic neurons was markedly elevated after prolonged expansion, resulting in large quantities of functional dopaminergic neurons without genetic modification. In restorative cell therapeutic approaches, midbrain‐derived neural progenitor cells reversed impaired motor function in rodents, survived well, and did not exhibit tumor formation in immunodeficient nude mice in the short or long term (8 and 30 weeks, respectively). We conclude that midbrain‐derived neural progenitor cells are a promising source for human dopaminergic neurons and suitable for long‐term expansion under good manufacturing practice, thus opening the avenue for restorative clinical applications or robust cellular models such as high‐content or high‐throughput screening. S<SMALL>TEM</SMALL> C<SMALL>ELLS</SMALL> T<SMALL>RANSLATIONAL</SMALL> M<SMALL>EDICINE</SMALL><I>2017;6:576–588</I></P>

Stem Cell Aging and Anti-aging Effects of Placenta Stem Cells on Aging

Jisook MOON 한국생물공학회 2015 한국생물공학회 학술대회 Vol.2015 No.10

한·중 소비자의 자민족중심주의와 외국기업의 전략적 CSR 활동

신지숙(Jisook Shin),문용호(Yongho Moon),천만봉(Manbong Cheon) 대한경영학회 2016 大韓經營學會誌 Vol.29 No.11

Impaired learning and memory in <i>Pitx3</i> deficient aphakia mice: A genetic model for striatum-dependent cognitive symptoms in Parkinson's disease

Ardayfio, Paul,Moon, JiSook,Leung, Ka Ka Amanda,Youn-Hwang, Dong,Kim, Kwang-Soo Elsevier 2008 Neurobiology of disease Vol.31 No.3

<P><B>Abstract</B></P><P>Disorders of the basal ganglia such as Parkinson's disease (PD) and Huntington's disease are commonly thought of primarily as motor disorders; however, the cognitive symptoms of these diseases such as executive dysfunction, learning, memory and attention deficits are prominent and often more disabling than the hallmark motor symptoms. Cognitive features of PD are often neglected in preclinical studies of PD, likely due to the lack of available animal models to study them. Aphakia mice, which are deficient in the transcription factor Pitx3, model the selective nigrostriatal DA loss in PD. Here we report that aphakia mice are impaired in striatum-dependent cognitive tasks including rotarod learning, T-maze and inhibitory avoidance tasks, but not the striatum-independent social transmission of food preference task. These results suggest that some neuropsychiatric symptoms in PD are related to the pathophysiology of the disease rather than stress associated with disease burden, or medications used to treat PD. Furthermore aphakia mice may be used as a novel model of non-motor symptoms in PD.</P>

The Effect of Attenuation and Scatter Correction in Rat Brain PET

Yu, A. R.,Jin Su Kim,Jisook Moon,Hee Joung Kim,Sang Moo Lim,Kyeong Min Kim IEEE 2013 IEEE transactions on nuclear science Vol.60 No.2

<P>Attenuation correction (AC) and scatter correction (SC) are problematic issues for animal positron emission tomography (PET). In this study, the effects of AC and SC were assessed using PET on a phantom and actual rat brain. Transmission (TX) was performed using <SUP>57</SUP>Co for 15 min. After a 15 min TX scan, emission (EM) PET was performed in list mode for 1 h. To assess the effects of AC and SC, the spillover ratio (SOR) was measured using a rat-sized NEMA NU4 image-quality phantom; statistical parametric mapping (SPM) was performed to assess the effects of AC and SC in the rat brain using 18<SUP>F</SUP>-FDG (FDG). In addition, the binding potential (BP) was compared for <SUP>18</SUP>F-FP-CIT (FP-CIT) PET. SPM was used to compare PET images to which AC and SC were applied, and BP was used for FP-CIT PET. The SORs of air and water decreased after AC and SC. SPM for FDG PET after AC showed a significant increase in FDG-measured activity in the cerebellum and occipital cortex. After AC/SC, a significant decrease in FDG-measured activity was observed in the frontal and temporal cortices. For FP-CIT PET of the rat brain, the BP decreased by 26% after AC because the FP-CIT uptake increased more in the cerebellum than in the striatum owing to AC. After AC and SC, the mean BP increased by 61%. AC and AC/SC were found to be necessary components of the artifact correction process for both FDG PET and FP-CIT PET of rat brains.</P>

Yin and Yang of disease genes and death genes between reciprocally scale-free biological networks

Han, Hyun Wook,Ohn, Jung Hun,Moon, Jisook,Kim, Ju Han Oxford University Press 2013 Nucleic acids research Vol.41 No.20

<P>Biological networks often show a scale-free topology with node degree following a power-law distribution. Lethal genes tend to form functional hubs, whereas non-lethal disease genes are located at the periphery. Uni-dimensional analyses, however, are flawed. We created and investigated two distinct scale-free networks; a protein–protein interaction (PPI) and a perturbation sensitivity network (PSN). The hubs of both networks exhibit a low molecular evolutionary rate (<I>P</I> < 8 × 10<SUP>−12</SUP>, <I>P</I> < 2 × 10<SUP>−4</SUP>) and a high codon adaptation index (<I>P</I> < 2 × 10<SUP>−16</SUP>, <I>P</I> < 2 × 10<SUP>−8</SUP>), indicating that both hubs have been shaped under high evolutionary selective pressure. Moreover, the topologies of PPI and PSN are inversely proportional: hubs of PPI tend to be located at the periphery of PSN and vice versa. PPI hubs are highly enriched with lethal genes but not with disease genes, whereas PSN hubs are highly enriched with disease genes and drug targets but not with lethal genes. PPI hub genes are enriched with essential cellular processes, but PSN hub genes are enriched with environmental interaction processes, having more TATA boxes and transcription factor binding sites. It is concluded that biological systems may balance internal growth signaling and external stress signaling by unifying the two opposite scale-free networks that are seemingly opposite to each other but work in concert between death and disease.</P>

Alpha-Synuclein Suppresses Retinoic Acid-Induced Neuronal Differentiation by Targeting the Glycogen Synthase Kinase-3β/β-Catenin Signaling Pathway

Kim, Sasuk,Lim, Juhee,Bang, Yeojin,Moon, Jisook,Kwon, Min-Soo,Hong, Jin Tae,Jeon, Jeha,Seo, Hyemyung,Choi, Hyun Jin Springer-Verlag 2018 Molecular Neurobiology Vol. No.

Nuclear receptor Nurr1 agonists enhance its dual functions and improve behavioral deficits in an animal model of Parkinson’s disease

Kim, Chun-Hyung,Han, Baek-Soo,Moon, Jisook,Kim, Deog-Joong,Shin, Joon,Rajan, Sreekanth,Nguyen, Quoc Toan,Sohn, Mijin,Kim, Won-Gon,Han, Minjoon,Jeong, Inhye,Kim, Kyoung-Shim,Lee, Eun-Hye,Tu, Yupeng,Naf National Academy of Sciences 2015 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF Vol.112 No.28

<P><B>Significance</B></P><P>Parkinson’s disease (PD) is the most prevalent movement disorder with no available treatments that can stop or slow down the disease progress. Although the orphan nuclear receptor Nurr1 is a promising target for PD, it is thought to be a ligand-independent transcription factor and, so far, no small molecule has been identified that can bind to its ligand binding domain. Here, we established high throughput cell-based assays and successfully identified three Nurr1 agonists among FDA-approved drugs, all sharing an identical chemical scaffold. Remarkably, these compounds not only directly bind to Nurr1 but also ameliorate behavioral defects in a rodent model of PD. Thus, our study shows that Nurr1 could serve as a valid drug target for neuroprotective therapeutics of PD.</P><P>Parkinson’s disease (PD), primarily caused by selective degeneration of midbrain dopamine (mDA) neurons, is the most prevalent movement disorder, affecting 1–2% of the global population over the age of 65. Currently available pharmacological treatments are largely symptomatic and lose their efficacy over time with accompanying severe side effects such as dyskinesia. Thus, there is an unmet clinical need to develop mechanism-based and/or disease-modifying treatments. Based on the unique dual role of the nuclear orphan receptor Nurr1 for development and maintenance of mDA neurons and their protection from inflammation-induced death, we hypothesize that Nurr1 can be a molecular target for neuroprotective therapeutic development for PD. Here we show successful identification of Nurr1 agonists sharing an identical chemical scaffold, 4-amino-7-chloroquinoline, suggesting a critical structure–activity relationship. In particular, we found that two antimalarial drugs, amodiaquine and chloroquine stimulate the transcriptional function of Nurr1 through physical interaction with its ligand binding domain (LBD). Remarkably, these compounds were able to enhance the contrasting dual functions of Nurr1 by further increasing transcriptional activation of mDA-specific genes and further enhancing transrepression of neurotoxic proinflammatory gene expression in microglia. Importantly, these compounds significantly improved behavioral deficits in 6-hydroxydopamine lesioned rat model of PD without any detectable signs of dyskinesia-like behavior. These findings offer proof of principle that small molecules targeting the Nurr1 LBD can be used as a mechanism-based and neuroprotective strategy for PD.</P>

Functional Roles of Nurr1, Pitx3, and Lmx1a in Neurogenesis and Phenotype Specification of Dopamine Neurons During In Vitro Differentiation of Embryonic Stem Cells

Hong, Sunghoi,Chung, Sangmi,Leung, Kaka,Hwang, Insik,Moon, Jisook,Kim, Kwang-Soo Mary Ann Liebert 2014 STEM CELLS AND DEVELOPMENT Vol.23 No.5

<P>To elucidate detailed functional mechanisms of key fate-determining transcription factors (eg, Nurr1, Pitx3, and Lmx1a) and their functional interplay for midbrain dopamine (mDA) neurons, we developed highly efficient gain-of-function system by transducing the neural progenitors (NPs) derived from embryonic stem cells (ESCs) with retroviral vectors, allowing the analysis of downstream molecular and cellular effects. Overexpression of each factors, Nurr1, Pitx3, and Lmx1a robustly promoted the dopaminergic differentiation of ESC-NP cells exposed to sonic hedgehog (SHH) and fibroblast growth factor 8 (FGF8). In addition, each of these factors directly interacts with potential binding sites within the tyrosine hydroxylase (TH) gene and activated its promoter activity. Interestingly, however, overexpression of Nurr1, but not of Pitx3 or Lmx1a, generated a significant number of nonneuronal TH-positive cells. In line with this, Pitx3 and Lmx1a, but not Nurr1, induced expression of the Ngn2 gene, which is critical for neurogenesis. We also observed that Pitx3 directly bound to its potential binding sites within the Ngn2 gene and the pan-neuronal marker β-tubulin III gene, suggesting that Pitx3 contributes to mDA neurogenesis by directly regulating these genes. Taken together, our data demonstrate that key mDA regulators (Nurr1, Pitx3, and Lmx1a) play overlapping as well as distinct roles during neurogenesis and neurotransmitter phenotype determination of mDA neurons.</P>

Adrenocortical carcinoma and a sporadic MEN1 mutation in a 3-year-old girl: a case report

Kim Sung Eun,Lee Na Yeong,Cho Won Kyoung,Yim Jisook,Lee Jae Wook,Kim Myungshin,Chung Jae Hee,Jung Min Ho,Suh Byung-Kyu,Ahn Moon Bae 대한소아내분비학회 2022 Annals of Pediatirc Endocrinology & Metabolism Vol.27 No.4

Childhood adrenocortical carcinoma (ACC) is a rare disease that is mostly linked to familial cancer syndrome. Although the prevalence of ACC is extremely low in children, it is clinically important to diagnose ACC early because age and tumor stage are closely related to prognosis. From this perspective, understanding the underlying genetics and possible symptoms of ACC is crucial in managing ACC with familial cancer syndromes. In this report, we present the case of a 3-year-old girl who initially presented with symptoms of precocious puberty and was later found to have ACC by imaging analysis. On genetic analysis, the patient was found to have a MEN1 gene mutation. MEN1 mutations are found in patients with multiple endocrine neoplasia type 1 (MEN1), usually precipitating multiple endocrine tumors, including pituitary adenoma, parathyroid hyperplasia, and adrenal tumors. Although MEN1 mutation is usually inherited in an autosomal dominant manner, neither of the patient’s parents had the same mutation, making hers a case of sporadic MEN1 mutation with initial presentation of ACC. The clinical course and further investigations of this patient are discussed in detail in this report.