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1
Baghchechi, Mohsen, Amy Plaia, Mary Hamer, Nirmalya Ghosh, Stephen Ashwal, and Andre Obenaus. "Susceptibility-Weighted Imaging Identifies Iron-Oxide-Labeled Human Neural Stem Cells: Automated Computational Detection." Developmental Neuroscience 38, no. 6 (2016): 445–57. http://dx.doi.org/10.1159/000455837.
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Neonatal hypoxic-ischemic brain injury (HII) can lead to devastating neurological outcomes such as cerebral palsy, epilepsy, and mental retardation. Human neural stem cell (hNSC) therapy provides new hope for the treatment of neonatal HII. These multipotent cells can aid in HII recovery by activating multiple reparative mechanisms including secretion of neurotrophic factors that enhance brain repair and plasticity. For clinical use of implanted hNSCs, methods are required to identify, quantify, track, and visualize migration and replication in an automated and reproducible fashion. In the current study, we used a model of unilateral HII in 10-day-old rat pups that were implanted with 250,000 Feridex-labeled hNSCs into the contralateral ventricle 3 days after HII. In addition to standard noninvasively acquired serial magnetic resonance imaging (MRI) sequences (11.7 and 4.7 T) that included diffusion-weighted imaging and T2-weighted imaging, we also acquired susceptibility-weighted imaging (SWI) 1-90 days after hNSC implantation. SWI is an advanced MRI method that enhances the visualization of iron-oxide-labeled hNSCs within affected regions of the injured neonatal brain. hNSC contrast was further enhanced by creating minimal intensity projections from the raw SWI magnitude images combined with phase information. Automated computational analysis using hierarchical region splitting (HRS) was applied for semiautomatic detection of hNSCs from SWI images. We found hNSCs in the ipsilateral HII lesion within the striatum and cortex adjacent to the lesion that corresponded to histological staining for iron. Quantitative phase values (radians) obtained from SWI revealed temporally evolving increased phase which reflects a decreased iron oxide content that is possibly related to cell division and the replicative capacity of the implanted hNSCs. SWI images also revealed hNSC migration from the contralateral injection site towards the ipsilateral HII lesion. Our results demonstrate that MRI-based SWI can monitor iron-labeled hNSCs in a clinically relevant manner and that automated computational methods such as HRS can rapidly identify iron-oxide-labeled hNSCs.
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Wang, Junwen, Ziyi Wang, Limeng Dai, Xintong Zhu, Xingying Guan, Junyi Wang, Jia Li, Mao Zhang, Yun Bai, and Hong Guo. "Supt16 Haploinsufficiency Impairs PI3K/AKT/mTOR/Autophagy Pathway in Human Pluripotent Stem Cells Derived Neural Stem Cells." International Journal of Molecular Sciences 24, no. 3 (February 3, 2023): 3035. http://dx.doi.org/10.3390/ijms24033035.
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The maintenance of neural stem cells (NSCs) plays a critical role in neurodevelopment and has been implicated in neurodevelopmental disorders (NDDs). However, the underlying mechanisms linking defective human neural stem cell self-renewal to NDDs remain undetermined. Our previous study found that Supt16 haploinsufficiency causes cognitive and social behavior deficits by disrupting the stemness maintenance of NSCs in mice. However, its effects and underlying mechanisms have not been elucidated in human neural stem cells (hNSCs). Here, we generated Supt16+/− induced pluripotent stem cells (iPSCs) and induced them into hNSCs. The results revealed that Supt16 heterozygous hNSCs exhibit impaired proliferation, cell cycle arrest, and increased apoptosis. As the RNA-seq analysis showed, Supt16 haploinsufficiency inhibited the PI3K/AKT/mTOR pathway, leading to rising autophagy, and further resulted in the dysregulated expression of multiple proteins related to cell proliferation and apoptotic process. Furthermore, the suppression of Supt16 heterozygous hNSC self-renewal caused by autophagy activation could be rescued by MHY1485 treatment or reproduced in rapamycin-treated hNSCs. Thus, our results showed that Supt16 was essential for hNSC self-renewal and its haploinsufficiency led to cell cycle arrest, impaired cell proliferation, and increased apoptosis of hNSCs by regulating the PI3K/AKT/mTOR/autophagy pathway. These provided a new insight to understand the causality between the Supt16 heterozygous NSCs and NDDs in humans.
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Helenes González, Citlali, Suwan N. Jayasinghe, and Patrizia Ferretti. "Bio-electrosprayed human neural stem cells are viable and maintain their differentiation potential." F1000Research 9 (April 17, 2020): 267. http://dx.doi.org/10.12688/f1000research.19901.1.
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Background: Bio-electrospray (BES) is a jet-based delivery system driven by an electric field that has the ability to form micro to nano-sized droplets. It holds great potential as a tissue engineering tool as it can be used to place cells into specific patterns. As the human central nervous system (CNS) cannot be studied in vivo at the cellular and molecular level, in vitro CNS models are needed. Human neural stem cells (hNSCs) are the CNS building block as they can generate both neurones and glial cells. Methods: Here we assessed for the first time how hNSCs respond to BES. To this purpose, different hNSC lines were sprayed at 10 kV and their ability to survive, grow and differentiate was assessed at different time points. Results: BES induced only a small and transient decrease in hNSC metabolic activity, from which cells recovered by day 6, and no significant increase in cell death was observed, as assessed by flow cytometry. Furthermore, bio-electrosprayed hNSCs differentiated as efficiently as controls into neurones, astrocytes and oligodendrocytes as shown by morphological, protein and gene expression analysis. Conclusions: This study highlights the robustness of hNSCs and identifies BES as a suitable technology that could be developed for the direct deposition of these cells in specific locations and configurations.
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Abedi, Mahsa, Mehrdad Hajinejad, Fereshteh Atabi, and Sajad Sahab-Negah. "Exosome Derived from Human Neural Stem Cells Improves Motor Activity and Neurogenesis in a Traumatic Brain Injury Model." BioMed Research International 2022 (August 12, 2022): 1–8. http://dx.doi.org/10.1155/2022/6409346.
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Traumatic brain injury (TBI) is a leading cause of mortality and long-lasting disability globally. Although novel treatment options have been investigated, no effective therapeutic opportunities for TBI exist. Accumulating studies demonstrated that the paracrine mechanisms of stem cells may allow them to orchestrate regenerative processes after TBI. So far, very little attention has been paid to the beneficial effects of human neural stem cells (hNSCs) in comparison to their exosomes as a paracrine mechanism. This study is aimed at comparing the effect of hNSCs with their exosomes in a TBI model. For in vitro assessments, we cultured hNSCs using the neurosphere method and isolated hNSC-derived exosomes from culture supernatants. For in vivo experiments, male rats were divided into three groups ( n = 8 /group): TBI group: rats were subjected to a unilateral mild cortical impact; hNSC group: rats received a single intralesional injection of 2 × 10 6 hNSCs after TBI; and exosome group: rats received a single intralesional injection of 63 μg protein of hNSC-derived exosomes after TBI. Neurological assessments, neuroinflammation, and neurogenesis were performed at the predetermined time points after TBI. Our results indicated that the administration of exosomes improved the neurobehavioral performance measured by the modified neurological severity score (mNSS) on day 28 after TBI. Furthermore, exosomes inhibited the expression of reactive astrocytes as a key regulator of neuroinflammation marked by GFAP at the protein level, while enhancing the expression of Doublecortin (DCX) as a neurogenesis marker at the mRNA level. On the other hand, we observed that the expression of stemness markers (SOX2 and Nestin) was elevated in the hNSC group compared to the exosome and TBI groups. To sum up, our results demonstrated that the superior effects of exosomes versus parent hNSCs could be mediated by improving mNSS score and increasing DCX in TBI. Considerably, more work will need to be done to determine the beneficial effects of exosomes versus parent cells in the context of TBI.
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Kim, Su Young, Hyoung-Soo Cho, Seung-Ha Yang, Jin-Young Shin, Jung-Sik Kim, and Chung-Gyu Park. "Exosomes secreted from human neural stem cells suppress T cell activation (90.33)." Journal of Immunology 182, no. 1_Supplement (April 1, 2009): 90.33. http://dx.doi.org/10.4049/jimmunol.182.supp.90.33.
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Abstract Exosomes are 50-100 nm diameter small membrane vesicles secreted from a variety of cells. Although exosomes express a common set of proteins, their protein composition is quite unique and varied significantly. Therefore, their function seems to be dynamic and determined by cell type specific proteins. Human neural stem cells (hNSCs) have been reported to have a therapeutic potential for neuro-regeneration in neurodegenerative disorders. However, the underlying mechanisms of neuroprotective effects of hNSCs are not still clear. In this study, we demonstrated that culture supernatant of hNSC, HB1.F3, can suppress the activation and proliferation of human T cells by apoptosis and cell cycle arrest. More interestingly, we found that exosomes secreted by hNSCs and included in culture supernatant play a critical role in the suppression of T cells by inducing G0/G1 arrest. Therefore, we here suggest that hNSCs has an immunomodulatory effect on T cells without cell-to-cell contact and a possible mechanism is mediated by secreted exosomes.
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Helenes González, Citlali, Suwan N. Jayasinghe, and Patrizia Ferretti. "Bio-electrosprayed human neural stem cells are viable and maintain their differentiation potential." F1000Research 9 (July 31, 2020): 267. http://dx.doi.org/10.12688/f1000research.19901.2.
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Background: Bio-electrospray (BES) is a jet-based delivery system driven by an electric field that has the ability to form micro to nano-sized droplets. It holds great potential as a tissue engineering tool as it can be used to place cells into specific patterns. As the human central nervous system (CNS) cannot be studied in vivo at the cellular and molecular level, in vitro CNS models are needed. Human neural stem cells (hNSCs) are the CNS building block as they can generate both neurones and glial cells. Methods: Here we assessed for the first time how hNSCs respond to BES. To this purpose, different hNSC lines were sprayed at 10 kV and their ability to survive, grow and differentiate was assessed at different time points. Results: BES induced only a small and transient decrease in hNSC metabolic activity, from which the cells recovered by day 6, and no significant increase in cell death was observed, as assessed by flow cytometry. Furthermore, bio-electrosprayed hNSCs differentiated as efficiently as controls into neurones, astrocytes and oligodendrocytes, as shown by morphological, protein and gene expression analysis. Conclusions: This study highlights the robustness of hNSCs and identifies BES as a suitable technology that could be developed for the direct deposition of these cells in specific locations and configurations.
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Huang, Chunli, and Jifeng Liu. "Identification of the Immune Cell Infiltration Landscape in Head and Neck Squamous Cell Carcinoma (HNSC) for the Exploration of Immunotherapy and Prognosis." Genetics Research 2022 (December 28, 2022): 1–15. http://dx.doi.org/10.1155/2022/6880760.
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It is generally believed that the majority of head and neck cancers develop in the mucosal epithelial cells of the mouth, pharynx, and larynx, which is collectively known as head and neck squamous cell carcinoma (HNSC). As a complex pathological process, HNSC develops through a variety of cellular and molecular events. Cancerous cells and immune cells infiltrating tumors are the main components of the tumor microenvironment. However, infiltration of HNSCs by the immune system has not been determined to date. In this work, we proposed computational algorithms to identify different immune subtypes. An analysis of the Cancer Genome Atlas (TCGA) database revealed gene expression profiles and corresponding clinical information. In HNSC patients, two immune-related genes (ZAP70 and IGKV2D-40) may be targets for immunotherapy, and these genes appear to be closely related to the prognosis. Several immunological subtypes were associated with immune function, immune checkpoints, and prognostic factors in HNSCs. Furthermore, ZAP70 is closely related to the overall survival (OS), progress-free interval (PFI), and disease-specific survival (DSS) of HNSC patients. The potential pathways that are associated with ZAP70 were found to have included adaptive immune response, response to oxidative stress, DNA replication, and lipid binding. This study provides a theoretical foundation for developing immunotherapy drugs for HNSC patients. By evaluating larger cohorts, we can gain a deeper understanding of immunotherapy and provide direction for current research on immunotherapy strategies in HNSCs.
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Greilach, Scott A., Laura L. McIntyre, Jonathan Hasselmann, Shivashankar Othy, Quy Ngyuen, Ilse Sears-Kraxberger, Oswald Steward, et al. "Human neural stem cells induce central nervous system specific regulatory T cells from the exTreg pool and promote repair in models of multiple sclerosis." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 160.3. http://dx.doi.org/10.4049/jimmunol.204.supp.160.3.
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Abstract Multiple Sclerosis (MS) is a chronic inflammatory autoimmune disease affecting the central nervous system (CNS) and for which there is no cure. Current treatments focus on suppression of the immune system but fail to repair the resulting damage to the CNS. Neural stem cell (NSC) transplantation is a promising therapeutic strategy for treating neurodegenerative diseases through cell replacement and repair however it is unclear how these cells would mediate repair in MS. We report that human NSCs promote CNS specific T regulatory cells (Tregs) which activate endogenous repair pathways and promote remyelination in a murine model of MS. We observed remyelination, decreased inflammation and an increase in (CNS)-infiltrating CD4+CD25+FoxP3+ Tregs in EAE mice receiving an intra-spinal transplant of hNSCs. Recovery was not a result of cell replacement, as hNSCs underwent xenograft rejection, and was Treg dependent, as ablation of Tregs abrogated histopathological improvement. Treg expansion is antigen driven as hNSCs expanded CD25+FoxP3+ Tregs in-vitro when cultured with neural antigen restricted RAG2−/−2D2+ (R2D2) splenocytes but not RAG2−/−OT-II+ splenocytes. When co-cultured with B6 splenocytes, hNSCs drove the expansion of unique TCRs when compared to controls. Additionally, hNSC-Tregs also appear to derive from the exTreg pool suggesting both antigen specific expansion and antigen dependent maintenance of FOXP3 in CNS-specific Tregs. hNSC Tregs also have a unique expression profile and express transglutimase-2 which is implicated in oligodendrocyte dependent repair in the CNS.
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Ghanekar, Yashoda, and Subhashini Sadasivam. "In silico analysis reveals a shared immune signature in CASP8-mutated carcinomas with varying correlations to prognosis." PeerJ 7 (February 11, 2019): e6402. http://dx.doi.org/10.7717/peerj.6402.
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Background Sequencing studies across multiple cancers continue to reveal mutations and genes involved in the pathobiology of these cancers. Exome sequencing of oral cancers, a subset of Head and Neck Squamous cell Carcinomas (HNSCs) common among tobacco-chewing populations, revealed that ∼34% of the affected patients harbor mutations in the CASP8 gene. Uterine Corpus Endometrial Carcinoma (UCEC) is another cancer where ∼10% cases harbor CASP8 mutations. Caspase-8, the protease encoded by CASP8 gene, plays a dual role in programmed cell death, which in turn has an important role in tumor cell death and drug resistance. CASP8 is a protease required for the extrinsic pathway of apoptosis and is also a negative regulator of necroptosis. Using multiple tools such as differential gene expression, gene set enrichment, gene ontology, in silico immune cell estimates, and survival analyses to mine data in The Cancer Genome Atlas, we compared the molecular features and survival of these carcinomas with and without CASP8 mutations. Results Differential gene expression followed by gene set enrichment analysis showed that HNSCs with CASP8 mutations displayed a prominent signature of genes involved in immune response and inflammation. Analysis of abundance estimates of immune cells in these tumors further revealed that mutant-CASP8 HNSCs were rich in immune cell infiltrates. However, in contrast to Human Papilloma Virus-positive HNSCs that also exhibit high immune cell infiltration, which in turn is correlated with better overall survival, HNSC patients with mutant-CASP8 tumors did not display any survival advantage. Similar analyses of UCECs revealed that while UCECs with CASP8 mutations also displayed an immune signature, they had better overall survival, in contrast to the HNSC scenario. There was also a significant up-regulation of neutrophils (p-value = 0.0001638) as well as high levels of IL33 mRNA (p-value = 7.63747E−08) in mutant-CASP8 HNSCs, which were not observed in mutant-CASP8 UCECs. Conclusions These results suggested that carcinomas with mutant CASP8 have broadly similar immune signatures albeit with different effects on survival. We hypothesize that subtle tissue-dependent differences could influence survival by modifying the micro-environment of mutant-CASP8 carcinomas. High neutrophil numbers, a well-known negative prognosticator in HNSCs, and/or high IL33 levels may be some of the factors affecting survival of mutant-CASP8 cases.
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Liu, Tingting, Xianwei Zeng, Fangling Sun, Hongli Hou, Yunqian Guan, Deyu Guo, Houxi Ai, Wen Wang, and Guojun Zhang. "EphB4 Regulates Self-Renewal, Proliferation and Neuronal Differentiation of Human Embryonic Neural Stem Cells in Vitro." Cellular Physiology and Biochemistry 41, no. 2 (2017): 819–34. http://dx.doi.org/10.1159/000459693.
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Background/Aims: EphB4 belongs to the largest family of Eph receptor tyrosine kinases. It contributes to a variety of pathological progresses of cancer malignancy. However, little is known about its role in neural stem cells (NSCs). This study examined whether EphB4 is required for proliferation and differentiation of human embryonic neural stem cells (hNSCs) in vitro. Methods: We up- and down-regulated EphB4 expression in hNSCs using lentiviral over-expression and shRNA knockdown constructs and then investigated the influence of EphB4 on the properties of hNSCs. Results: Our results show that shRNA-mediated EphB4 reduction profoundly impaired hNSCs self-renewal and proliferation. Furthermore, detection of differentiation revealed that knockdown of EphB4 inhibited hNSCs differentiation towards a neuronal lineage and promoted hNSCs differentiation to glial cells. In contrast, EphB4 overexpression promoted hNSCs self-renewal and proliferation, further induced hNSCs differentiation towards a neuronal lineage and inhibited hNSCs differentiation to glial cells. Moreover, we found that EphB4 regulates cell proliferation mediated by the Abl-CyclinD1 pathway. Conclusion: These studies provide strong evidence that fine tuning of EphB4 expression is crucial for the proliferation and neuronal differentiation of hNSCs, suggesting that EphB4 might be an interesting target for overcoming some of the therapeutic limitations of neuronal loss in brain diseases.
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Han, Xinxin, Liming Yu, Jie Ren, Min Wang, Zhongliang Liu, Xinyu Hu, Daiyu Hu, et al. "Efficient and Fast Differentiation of Human Neural Stem Cells from Human Embryonic Stem Cells for Cell Therapy." Stem Cells International 2017 (2017): 1–11. http://dx.doi.org/10.1155/2017/9405204.
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Stem cell-based therapies have been used for repairing damaged brain tissue and helping functional recovery after brain injury. Aberrance neurogenesis is related with brain injury, and multipotential neural stem cells from human embryonic stem (hES) cells provide a great promise for cell replacement therapies. Optimized protocols for neural differentiation are necessary to produce functional human neural stem cells (hNSCs) for cell therapy. However, the qualified procedure is scarce and detailed features of hNSCs originated from hES cells are still unclear. In this study, we developed a method to obtain hNSCs from hES cells, by which we could harvest abundant hNSCs in a relatively short time. Then, we examined the expression of pluripotent and multipotent marker genes through immunostaining and confirmed differentiation potential of the differentiated hNSCs. Furthermore, we analyzed the mitotic activity of these hNSCs. In this report, we provided comprehensive features of hNSCs and delivered the knowledge about how to obtain more high-quality hNSCs from hES cells which may help to accelerate the NSC-based therapies in brain injury treatment.
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Park, Minah, Mikyung Shin, Eunmi Kim, Slgirim Lee, Kook In Park, Haeshin Lee, and Jae-Hyung Jang. "The Promotion of Human Neural Stem Cells Adhesion Using Bioinspired Poly(norepinephrine) Nanoscale Coating." Journal of Nanomaterials 2014 (2014): 1–10. http://dx.doi.org/10.1155/2014/793052.
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The establishment of versatile biomaterial interfaces that can facilitate cellular adhesion is crucial for elucidating the cellular processes that occur on biomaterial surfaces. Furthermore, biomaterial interfaces can provide physical or chemical cues that are capable of stimulating cellular behaviors by regulating intracellular signaling cascades. Herein, a method of creating a biomimetic functional biointerface was introduced to enhance human neural stem cell (hNSC) adhesion. The hNSC-compatible biointerface was prepared by the oxidative polymerization of the neurotransmitter norepinephrine, which generates a nanoscale organic thin layer, termed poly(norepinephrine) (pNE). Due to its adhesive property, pNE resulted in an adherent layer on various substrates, and pNE-coated biointerfaces provided a highly favorable microenvironment for hNSCs, with no observed cytotoxicity. Only a 2-hour incubation of hNSCs was required to firmly attach the stem cells, regardless of the type of substrate. Importantly, the adhesive properties of pNE interfaces led to micropatterns of cellular attachment, thereby demonstrating the ability of the interface to organize the stem cells. This highly facile surface-modification method using a biomimetic pNE thin layer can be applied to a number of suitable materials that were previously not compatible with hNSC technology.
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Sun, Lei, Fan Wang, Heng Chen, Dong Liu, Tingyu Qu, Xiaofeng Li, Daxia Xu, Feng Liu, Zhanmin Yin, and Yunzhen Chen. "Co-Transplantation of Human Umbilical Cord Mesenchymal Stem Cells and Human Neural Stem Cells Improves the Outcome in Rats with Spinal Cord Injury." Cell Transplantation 28, no. 7 (April 23, 2019): 893–906. http://dx.doi.org/10.1177/0963689719844525.
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Neural stem cells (NSCs) and mesenchymal stem cells (MSCs) are promising graft materials for cell therapies in spinal cord injury (SCI) models. Previous studies have demonstrated that MSCs can regulate the microenvironment of NSCs and promote their survival rate. Furthermore, several studies indicate that MSCs can reduce stem cell transplantation-linked tumor formation. To our knowledge, no previous studies have determined whether co-transplantation of human umbilical cord mesenchymal stem cells (hUC-MSCs) and human neural stem cells (hNSCs) could improve the outcome in rats with SCI. Therefore, we investigated whether the transplantation of hUC-MSCs combined with hNSCs through an intramedullary injection can improve the outcome of rats with SCI, and explored the underlying mechanisms. In this study, a moderate spinal cord contusion model was established in adult female Wistar rats using an NYU impactor. In total, 108 spinal cord-injured rats were randomly selected and divided into the following five groups: 1) hUC-MSCs group, 2) hNSCs group, 3) hUC-MSCs+hNSCs group, 4) PBS (control) group, and 5) a Sham group. Basso, Beattie and Bresnahan (BBB) behavioral test scores were used to evaluate the motor function of all animals before and after the SCI weekly through the 8th week. Two weeks after transplantation, some rats were sacrificed, immunofluorescence and immunohistochemistry were performed to evaluate the survival and differentiation of the transplanted stem cells, and brain-derived neurotrophic factor (BDNF) was detected by ELISA in the injured spinal cords. At the end of the experiment, we evaluated the remaining myelin sheath and anterior horn neurons in the injured spinal cords using Luxol Fast Blue (LFB) staining. Our results demonstrated that the surviving stem cells in the hUC-MSCs+hNSCs group were significantly increased compared with those in the hUC-MSCs alone and the hNSCs alone groups 2 weeks post-transplantation. Furthermore, the results of the BBB scores and the remaining myelin sheath evaluated via LFB staining in the injured spinal cords demonstrated that the most significantly improved outcome occurred in the hUC-MSCs+hNSCs group. The hUC-MSCs alone and the hNSCs alone groups also had a better outcome compared with that of the PBS-treated group. In conclusion, the present study demonstrates that local intramedullary subacute transplantation of hUC-MSCs, hNSCs, or hUC-MSCs+hNSCs significantly improves the outcome in an in vivo moderate contusion SCI model, and that co-transplantation of hUC-MSCs and hNSCs displayed the best outcome in our experiment.
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Grespi, Valentina, Cecilia Caprera, Claudia Ricciolini, Ilaria Bicchi, Gianmarco Muzi, Matteo Corsi, Stefano Ascani, Angelo Luigi Vescovi, and Maurizio Gelati. "Human neural stem cells drug product: Microsatellite instability analysis." PLOS ONE 17, no. 8 (August 30, 2022): e0273679. http://dx.doi.org/10.1371/journal.pone.0273679.
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Introduction In central nervous system neurodegenerative disorders, stem cell-based therapies should be considered as a promising therapeutic approach. The safe use of human Neural Stem Cells (hNSCs) for the treatment of several neurological diseases is currently under evaluation of phase I/II clinical trials. Clinical application of hNSCs require the development of GMP standardized protocols capable of generating high quantities of reproducible and well characterized stem cells bearing stable functional and genetic properties. Aim The aim of this study was to evaluate possible instabilities or modifications of the microsatellite loci in different culture passages because high culture passages represent an in vitro replicative stress leading to senescence. Experimental method: The hNSCs were characterized at different culture time points, from passage 2 to passage 25, by genetic typing at ten microsatellite loci. Conclusion We showed that genetic stability at microsatellite loci is maintained by the cells even at high passages adding a further demonstration of the safety of our hNSCs GMP culture method.
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Roitberg, Ben Z., Erwin Mangubat, Er-Yun Chen, Kiminobu Sugaya, Keith R. Thulborn, Jeffrey H. Kordower, Ambarish Pawar, Todd Konecny, and Marina E. Emborg. "Survival and early differentiation of human neural stem cells transplanted in a nonhuman primate model of stroke." Journal of Neurosurgery 105, no. 1 (July 2006): 96–102. http://dx.doi.org/10.3171/jns.2006.105.1.96.
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Object Neural cell transplantation has been proposed as a treatment after stroke. The purpose of this study was to establish if human neural stem cells (HNSCs) could survive in the nonhuman primate brain after an ischemic event. Methods Three adult cynomolgus monkeys received a unilateral occlusion of the M1 segment of the right middle cerebral artery (MCA). One week later each animal received five magnetic resonance (MR) image–guided stereotactic intracerebral injections of HNSC neurospheres labeled with bromodeoxyuridine (BrdU) in the areas surrounding the ischemic lesion as defined in T1- and T2-weighted images. On the day of transplantation and throughout the study the monkeys received oral cyclosporine (10 mg/kg twice a day), and plasma levels were monitored routinely. The animals were killed at 45, 75, or 105 days after transplantation. Magnetic resonance images revealed a cortical and subcortical infarction in the MCA distribution area. Postmortem morphological brain analyses confirmed the distribution of the infarcted area seen in the MR images, with loss of tissue and necrosis in the ischemic region. Cells that were positive for BrdU were present in the three experimental monkeys, mainly along injection tracks. Double-label immuno-fluorescence for BrdU and βIII-tubulin (a marker of young neurons) revealed colocalization of few HNSCs, most of which were observed outside the immediate injection site. Colocalization with nestin was also observed, indicating an early neural/glial fate. Conclusions In a model of stroke in nonhuman primates, HNSCs can survive up to 105 days when transplanted 1 week after an ischemic event and can partly undergo neuronal differentiation.
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Kutikov, Artem B., Simon W. Moore, Richard T. Layer, Pamela E. Podell, Nithya Sridhar, Andrea J. Santamaria, Alex A. Aimetti, Christoph P. Hofstetter, Thomas R. Ulich, and James D. Guest. "Method and Apparatus for the Automated Delivery of Continuous Neural Stem Cell Trails Into the Spinal Cord of Small and Large Animals." Neurosurgery 85, no. 4 (August 29, 2018): 560–73. http://dx.doi.org/10.1093/neuros/nyy379.
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AbstractBackgroundImmature neurons can extend processes after transplantation in adult animals. Neuronal relays can form between injected neural stem cells (NSCs) and surviving neurons, possibly improving recovery after spinal cord injury (SCI). Cell delivery methods of single or multiple bolus injections of concentrated cell suspensions thus far tested in preclinical and clinical experiments are suboptimal for new tract formation. Nonuniform injectate dispersal is often seen due to gravitational cell settling and clumping. Multiple injections have additive risks of hemorrhage, parenchymal damage, and cellular reflux and require additional surgical exposure. The deposition of multiply delivered cells boluses may be uneven and discontinuous.ObjectiveTo develop an injection apparatus and methodology to deliver continuous cellular trails bridging spinal cord lesions.MethodsWe improved the uniformity of cellular trails by formulating NSCs in hyaluronic acid. The TrailmakerTM stereotaxic injection device was automatized to extend a shape memory needle from a single-entry point in the spinal cord longitudinal axis to “pioneer” a new trail space and then retract while depositing an hyaluronic acid-NSC suspension. We conducted testing in a collagen spinal models, and animal testing using human NSCs (hNSCs) in rats and minipigs.ResultsContinuous surviving trails of hNSCs within rat and minipig naive spinal cords were 12 and 40 mm in length. hNSC trails were delivered across semi-acute contusion injuries in rats. Transplanted hNSCs survived and were able to differentiate into neural lineage cells and astrocytes.CONCLUSIONThe TrailmakerTM creates longitudinal cellular trails spanning multiple levels from a single-entry point. This may enhance the ability of therapeutics to promote functional relays after SCI.
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Riccetti, Silvia, Alessandro Sinigaglia, Giovanna Desole, Norbert Nowotny, Marta Trevisan, and Luisa Barzon. "Modelling West Nile Virus and Usutu Virus Pathogenicity in Human Neural Stem Cells." Viruses 12, no. 8 (August 12, 2020): 882. http://dx.doi.org/10.3390/v12080882.
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West Nile virus (WNV) and Usutu virus (USUV) are genetically related neurotropic mosquito-borne flaviviruses, which frequently co-circulate in nature. Despite USUV seeming to be less pathogenic for humans than WNV, the clinical manifestations induced by these two viruses often overlap and may evolve to produce severe neurological complications. The aim of this study was to investigate the effects of WNV and USUV infection on human induced pluripotent stem cell-derived neural stem cells (hNSCs), as a model of the neural progenitor cells in the developing fetal brain and in adult brain. Zika virus (ZIKV), a flavivirus with known tropism for NSCs, was used as the positive control. Infection of hNSCs and viral production, effects on cell viability, apoptosis, and innate antiviral responses were compared among viruses. WNV displayed the highest replication efficiency and cytopathic effects in hNSCs, followed by USUV and then ZIKV. In these cells, both WNV and USUV induced the overexpression of innate antiviral response genes at significantly higher levels than ZIKV. Expression of interferon type I, interleukin-1β and caspase-3 was significantly more elevated in WNV- than USUV-infected hNSCs, in agreement with the higher neuropathogenicity of WNV and the ability to inhibit the interferon response pathway.
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Marchini, Amanda, Andrea Raspa, Raffaele Pugliese, Marina Abd El Malek, Valentina Pastori, Marzia Lecchi, Angelo L. Vescovi, and Fabrizio Gelain. "Multifunctionalized hydrogels foster hNSC maturation in 3D cultures and neural regeneration in spinal cord injuries." Proceedings of the National Academy of Sciences 116, no. 15 (March 28, 2019): 7483–92. http://dx.doi.org/10.1073/pnas.1818392116.
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Three-dimensional cell cultures are leading the way to the fabrication of tissue-like constructs useful to developmental biology and pharmaceutical screenings. However, their reproducibility and translational potential have been limited by biomaterial and culture media compositions, as well as cellular sources. We developed a construct comprising synthetic multifunctionalized hydrogels, serum-free media, and densely seeded good manufacturing practice protocol-grade human neural stem cells (hNSC). We tracked hNSC proliferation, differentiation, and maturation into GABAergic, glutamatergic, and cholinergic neurons, showing entangled electrically active neural networks. The neuroregenerative potential of the “engineered tissue” was assessed in spinal cord injuries, where hNSC-derived progenitors and predifferentiated hNSC progeny, embedded in multifunctionalized hydrogels, were implanted. All implants decreased astrogliosis and lowered the immune response, but scaffolds with predifferentiated hNSCs showed higher percentages of neuronal markers, better hNSC engraftment, and improved behavioral recovery. Our hNSC-construct enables the formation of 3D functional neuronal networks in vitro, allowing novel strategies for hNSC therapies in vivo.
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Ruiz-Perera, Lucia Mercedes, Johannes Friedrich Wilhelm Greiner, Christian Kaltschmidt, and Barbara Kaltschmidt. "A Matter of Choice: Inhibition of c-Rel Shifts Neuronal to Oligodendroglial Fate in Human Stem Cells." Cells 9, no. 4 (April 22, 2020): 1037. http://dx.doi.org/10.3390/cells9041037.
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The molecular mechanisms underlying fate decisions of human neural stem cells (hNSCs) between neurogenesis and gliogenesis are critical during neuronal development and neurodegenerative diseases. Despite its crucial role in the murine nervous system, the potential role of the transcription factor NF-κB in the neuronal development of hNSCs is poorly understood. Here, we analyzed NF-κB subunit distribution during glutamatergic differentiation of hNSCs originating from neural crest-derived stem cells. We observed several peaks of specific NF-κB subunits. The most prominent nuclear peak was shown by c-REL subunit during a period of 2–5 days after differentiation onset. Furthermore, c-REL inhibition with pentoxifylline (PTXF) resulted in a complete shift towards oligodendroglial fate, as demonstrated by the presence of OLIG2+/O4+-oligodendrocytes, which showed PDGFRα, NG2 and MBP at the transcript level. In addition c-REL impairment further produced a significant decrease in neuronal survival. Transplantation of PTXF-treated predifferentiated hNSCs into an ex vivo oxidative-stress-mediated demyelination model of mouse organotypic cerebellar slices further led to integration in the white matter and differentiation into MBP+ oligodendrocytes, validating their functionality and therapeutic potential. In summary, we present a human cellular model of neuronal differentiation exhibiting a novel essential function of NF-κB-c-REL in fate choice between neurogenesis and oligodendrogenesis which will potentially be relevant for multiple sclerosis and schizophrenia.
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Profico, Daniela Celeste, Maurizio Gelati, Daniela Ferrari, Giada Sgaravizzi, Claudia Ricciolini, Massimo Projetti Pensi, Gianmarco Muzi, et al. "Human Neural Stem Cell-Based Drug Product: Clinical and Nonclinical Characterization." International Journal of Molecular Sciences 23, no. 21 (November 3, 2022): 13425. http://dx.doi.org/10.3390/ijms232113425.
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Translation of cell therapies into clinical practice requires the adoption of robust production protocols in order to optimize and standardize the manufacture and cryopreservation of cells, in compliance with good manufacturing practice regulations. Between 2012 and 2020, we conducted two phase I clinical trials (EudraCT 2009-014484-39, EudraCT 2015-004855-37) on amyotrophic lateral sclerosis secondary progressive multiple sclerosis patients, respectively, treating them with human neural stem cells. Our production process of a hNSC-based medicinal product is the first to use brain tissue samples extracted from fetuses that died in spontaneous abortion or miscarriage. It consists of selection, isolation and expansion of hNSCs and ends with the final pharmaceutical formulation tailored to a specific patient, in compliance with the approved clinical protocol. The cells used in these clinical trials were analyzed in order to confirm their microbiological safety; each batch was also tested to assess identity, potency and safety through morphological and functional assays. Preclinical, clinical and in vitro nonclinical data have proved that our cells are safe and stable, and that the production process can provide a high level of reproducibility of the cultures. Here, we describe the quality control strategy for the characterization of the hNSCs used in the above-mentioned clinical trials.
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Iwata, Kengo, Farhana Ferdousi, Yoshinobu Arai, and Hiroko Isoda. "Interactions between Major Bioactive Polyphenols of Sugarcane Top: Effects on Human Neural Stem Cell Differentiation and Astrocytic Maturation." International Journal of Molecular Sciences 23, no. 23 (December 1, 2022): 15120. http://dx.doi.org/10.3390/ijms232315120.
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Sugarcane (Saccharum officinarum L.) is a tropical plant grown for sugar production. We recently showed that sugarcane top (ST) ameliorates cognitive decline in a mouse model of accelerated aging via promoting neuronal differentiation and neuronal energy metabolism and extending the length of the astrocytic process in vitro. Since the crude extract consists of multicomponent mixtures, it is crucial to identify bioactive compounds of interest and the affected molecular targets. In the present study, we investigated the bioactivities of major polyphenols of ST, namely 3-O-caffeoylquinic acid (3CQA), 5-O-caffeoylquinic acid (5CQA), 3-O-feruloylquinic acid (3FQA), and Isoorientin (ISO), in human fetal neural stem cells (hNSCs)- an in vitro model system for studying neural development. We found that multiple polyphenols of ST contributed synergistically to stimulate neuronal differentiation of hNSCs and induce mitochondrial activity in immature astrocytes. Mono-CQAs (3CQA and 5CQA) regulated the expression of cyclins related to G1 cell cycle arrest, whereas ISO regulated basic helix-loop-helix transcription factors related to cell fate determination. Additionally, mono-CQAs activated p38 and ISO inactivated GSK3β. In hNSC-derived immature astrocytes, the compounds upregulated mRNA expression of PGC-1α, a master regulator of astrocytic mitochondrial biogenesis. Altogether, our findings suggest that synergistic interactions between major polyphenols of ST contribute to its potential for neuronal differentiation and astrocytic maturation.
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Fujita, Yosuke, Tomoki Nagakura, Hiroyuki Uchino, Masato Inazu, and Tsuyoshi Yamanaka. "Functional Expression of Choline Transporters in Human Neural Stem Cells and Its Link to Cell Proliferation, Cell Viability, and Neurite Outgrowth." Cells 10, no. 2 (February 20, 2021): 453. http://dx.doi.org/10.3390/cells10020453.
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Choline and choline metabolites are essential for all cellular functions. They have also been reported to be crucial for neural development. In this work, we studied the functional characteristics of the choline uptake system in human neural stem cells (hNSCs). Additionally, we investigated the effect of extracellular choline uptake inhibition on the cellular activities in hNSCs. We found that the mRNAs and proteins of choline transporter-like protein 1 (CTL1) and CTL2 were expressed at high levels. Immunostaining showed that CTL1 and CTL2 were localized in the cell membrane and partly in the mitochondria, respectively. The uptake of extracellular choline was saturable and performed by a single uptake mechanism, which was Na+-independent and pH-dependent. We conclude that CTL1 is responsible for extracellular choline uptake, and CTL2 may uptake choline in the mitochondria and be involved in DNA methylation via choline oxidation. Extracellular choline uptake inhibition caused intracellular choline deficiency in hNSCs, which suppressed cell proliferation, cell viability, and neurite outgrowth. Our findings contribute to the understanding of the role of choline in neural development as well as the pathogenesis of various neurological diseases caused by choline deficiency or choline uptake impairment.
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Shang, Weihu, Xiaoyan Zhang, Mo Zhang, Zetan Fan, Ying Sun, Mei Han, and Louzhen Fan. "The uptake mechanism and biocompatibility of graphene quantum dots with human neural stem cells." Nanoscale 6, no. 11 (2014): 5799–806. http://dx.doi.org/10.1039/c3nr06433f.
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He, Zhenghui, Lijian Lang, Jiyuan Hui, Yuxiao Ma, Chun Yang, Weiji Weng, Jialin Huang, et al. "Brain Extract of Subacute Traumatic Brain Injury Promotes the Neuronal Differentiation of Human Neural Stem Cells via Autophagy." Journal of Clinical Medicine 11, no. 10 (May 11, 2022): 2709. http://dx.doi.org/10.3390/jcm11102709.
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Background: After a traumatic brain injury (TBI), the cell environment is dramatically changed, which has various influences on grafted neural stem cells (NSCs). At present, these influences on NSCs have not been fully elucidated, which hinders the finding of an optimal timepoint for NSC transplantation. Methods: Brain extracts of TBI mice were used in vitro to simulate the different phase TBI influences on the differentiation of human NSCs. Protein profiles of brain extracts were analyzed. Neuronal differentiation and the activation of autophagy and the WNT/CTNNB pathway were detected after brain extract treatment. Results: Under subacute TBI brain extract conditions, the neuronal differentiation of hNSCs was significantly higher than that under acute brain extract conditions. The autophagy flux and WNT/CTNNB pathway were activated more highly within the subacute brain extract than in the acute brain extract. Autophagy activation by rapamycin could rescue the neuronal differentiation of hNSCs within acute TBI brain extract. Conclusions: The subacute phase around 7 days after TBI in mice could be a candidate timepoint to encourage more neuronal differentiation after transplantation. The autophagy flux played a critical role in regulating neuronal differentiation of hNSCs and could serve as a potential target to improve the efficacy of transplantation in the early phase.
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Zhao, Yixuan, Xin Huang, Zewei Zhang, Haizhou Li, and Tao Zan. "The Long Noncoding Transcript HNSCAT1 Activates KRT80 and Triggers Therapeutic Efficacy in Head and Neck Squamous Cell Carcinoma." Oxidative Medicine and Cellular Longevity 2022 (August 4, 2022): 1–19. http://dx.doi.org/10.1155/2022/4156966.
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Head and neck squamous carcinoma (HNSC) is the most prevalent malignancy of the head and neck regions. Long noncoding RNAs (lncRNAs) are vital in tumorigenesis regulation. However, the role of lncRNAs in HNSC requires further exploration. Herein, through bioinformatic assays using The Cancer Genome Atlas (TCGA) datasets, rapid amplification of cDNA ends (RACE) assays, and RNA-FISH, we revealed that a novel cytoplasmic transcript, HNSC-associated transcript 1 (HNSCAT1, previously recognized as linc01269), was downregulated in tumor samples and advanced tumor stages and was also associated with favorable outcomes in HNSC. Overexpression of HNSCAT1 triggered treatment efficacy in HNSCs both in vivo and in vitro. More importantly, through high-throughput transcriptome analysis (RNA-seq, in NODE database, OEZ007550), we identified KRT80, a tumor suppressor in HNSC, as the target of HNSCAT1. KRT80 expression was modulated by lncRNA HNSCAT1 and presented a positive correlation in tumor samples ( R = 0.52 , p < 0.001 ). Intriguingly, we identified that miR-1245 simultaneously interacts with KRT80 and HNSCAT1, which bridges the regulatory function between KRT80 and HNSCAT1. Conclusively, our study demonstrated that lncRNA HNSCAT1 functions as a necessary tumor inhibitor in HNSC, which provides a novel mechanism of lncRNA function and provides alternative targets for the diagnosis and treatment of HNSC.
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Acharya, Munjal M., Lori-Ann Christie, Thomas G. Hazel, Karl K. Johe, and Charles L. Limoli. "Transplantation of Human Fetal-Derived Neural Stem Cells Improves Cognitive Function following Cranial Irradiation." Cell Transplantation 23, no. 10 (October 2014): 1255–66. http://dx.doi.org/10.3727/096368913x670200.
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Treatment of central nervous system (CNS) malignancies typically involves radiotherapy to forestall tumor growth and recurrence following surgical resection. Despite the many benefits of cranial radiotherapy, survivors often suffer from a wide range of debilitating and progressive cognitive deficits. Thus, while patients afflicted with primary and secondary malignancies of the CNS now experience longer local regional control and progression-free survival, there remains no clinical recourse for the unintended neurocognitive sequelae associated with their cancer treatments. Multiple mechanisms contribute to disrupted cognition following irradiation, including the depletion of radiosensitive populations of stem and progenitor cells in the hippocampus. We have explored the potential of using intrahippocampal transplantation of human stem cells to ameliorate radiation-induced cognitive dysfunction. Past studies demonstrated the capability of cranially transplanted human embryonic (hESCs) and neural (hNSCs) stem cells to functionally restore cognition in rats 1 and 4 months after cranial irradiation. The present study employed an FDA-approved fetal-derived hNSC line capable of large scale-up under good manufacturing practice (GMP). Animals receiving cranial transplantation of these cells 1 month following irradiation showed improved hippocampal spatial memory and contextual fear conditioning performance compared to irradiated, sham surgery controls. Significant newly born (doublecortin positive) neurons and a smaller fraction of glial subtypes were observed within and nearby the transplantation core. Engrafted cells migrated and differentiated into neuronal and glial subtypes throughout the CA1 and CA3 subfields of the host hippocampus. These studies expand our prior findings to demonstrate that transplantation of fetal-derived hNSCs improves cognitive deficits in irradiated animals, as assessed by two separate cognitive tasks.
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Cho, Younghak, Jieung Baek, Eunjung Lee, and Sung Gap Im. "Heparin-mediated electrostatic immobilization of bFGF via functional polymer films for enhanced self-renewal of human neural stem cells." Journal of Materials Chemistry B 9, no. 8 (2021): 2084–91. http://dx.doi.org/10.1039/d0tb02799e.
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A novel copolymer film of pGMA-co-DMAEMA is generated to modulate the electrostatic interaction with heparin, thereby facilitating bFGF immobilization. hNSCs cultured on this surface exhibited enhanced stemness-related properties and neurogenesis.
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Huang, Hesen, Yu Du, Dean Zhao, and Kaiqin Chen. "The Relationship between the Prognostic Marker LIMA1 in Head and Neck Squamous Cell Carcinoma and Immune Infiltration." Journal of Oncology 2022 (August 31, 2022): 1–14. http://dx.doi.org/10.1155/2022/1040116.
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Background. Head and neck squamous cell carcinoma (HNSC) is one of the most common malignancies, and identification of HNSC biomarkers is critical. LIM Domain And Actin Binding 1 (LIMA1) is involved in actin cytoskeleton regulation and dynamics. The role of LIMA1 in HNSC is unclear. This is the first study to investigate the expression of LIMA1 in HNSC patients and its prognostic value, potential biological functions, and impact on the immune system. Methods. Gene expression and clinicopathological analysis, enrichment analysis, and immune infiltration analysis were all based on data from The Cancer Genome Atlas (TCGA) with additional bioinformatics analysis. Statistical analysis was performed using TIMER and ssGSEA to analyze the immune response to LIMA1 expression in HNSCs. In addition, Gene Expression Omnibus (GEO), Kaplan–Meier(K-M) survival analysis, and data from the Human Protein Atlas (HPA) were used to validate the results. Results. LIMA1 played a key role as an independent prognostic factor in HNSC patients. GSEA found that LIMA1 is associated with promoting cell adhesion and suppressing immune function. LIMA1 expression was significantly correlated with infiltration of B cells, CD8+ T cells, CD4+ T cells, dendritic cells, and neutrophils and was coexpressed with immune-related genes and immune checkpoints. Conclusion. The expression of LIMA1 is increased in HNSC, and the high expression of LIMA1 is associated with poor prognosis. LIMA1 may affect tumor development by regulating tumor-infiltrating cells in the tumor microenvironment (TME). LIMA1 may be a potential target for immunotherapy.
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Lilja, Anna M., Linn Malmsten, Jennie Röjdner, Larysa Voytenko, Alexei Verkhratsky, Sven Ove Ögren, Agneta Nordberg, and Amelia Marutle. "Neural Stem Cell Transplant-Induced Effect on Neurogenesis and Cognition in Alzheimer Tg2576 Mice Is Inhibited by Concomitant Treatment with Amyloid-Lowering or Cholinergicα7 Nicotinic Receptor Drugs." Neural Plasticity 2015 (2015): 1–13. http://dx.doi.org/10.1155/2015/370432.
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Stimulating regeneration in the brain has the potential to rescue neuronal networks and counteract progressive pathological changes in Alzheimer’s disease (AD). This study investigated whether drugs with different mechanisms of action could enhance neurogenesis and improve cognition in mice receiving human neural stem cell (hNSC) transplants. Six- to nine-month-old AD Tg2576 mice were treated for five weeks with the amyloid-modulatory and neurotrophic drug (+)-phenserine or with the partialα7 nicotinic receptor (nAChR) agonist JN403, combined with bilateral intrahippocampal hNSC transplantation. We observed improved spatial memory in hNSC-transplanted non-drug-treated Tg2576 mice but not in those receiving drugs, and this was accompanied by an increased number of Doublecortin- (DCX-) positive cells in the dentate gyrus, a surrogate marker for newly generated neurons. Treatment with (+)-phenserine did however improve graft survival in the hippocampus. An accumulation ofα7 nAChR-expressing astrocytes was observed around the injection site, suggesting their involvement in repair and scarring processes. Interestingly, JN403 treatment decreased the number ofα7 nAChR-expressing astrocytes, correlating with a reduction in the number of DCX-positive cells in the dentate gyrus. We conclude that transplanting hNSCs enhances endogenous neurogenesis and prevents further cognitive deterioration in Tg2576 mice, while simultaneous treatments with (+)-phenserine or JN403 result in countertherapeutic effects.
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Kharazi, Alex, Michael L. Levy, Maria Cristina Visperas, and Chih-Min Lin. "Chicken embryonic brain: an in vivo model for verifying neural stem cell potency." Journal of Neurosurgery 119, no. 2 (August 2013): 512–19. http://dx.doi.org/10.3171/2013.1.jns12698.
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Object The multipotency of neural stem cells (NSCs) can be assessed in vitro by detection of stage-specific markers in response to a suitable differentiation signal. This test is frequently used because it is fast and affordable. However, it is not clear how the in vitro potential for multilineage differentiation and stem cell marker expression would reflect the ability of NSCs to engraft into the brain following transplantation. The authors undertook this study to directly compare the in vitro potency and in vivo migration of human NSCs (hNSCs) expanded under conditions of gradually increased concentration of fetal bovine serum (FBS) as a maturation factor. Methods Human NSCs isolated from fetal brain were propagated in serum free media (SF-hNSCs) and in media containing 0.1% and 0.2% serum. At Passage 4 in tissue culture the NSCs were harvested and either differentiated in vitro or transplanted into the lateral ventricle of chicken embryonic brain at the late stage of its development (Hamburger and Hamilton Stage 26). The in vitro differentiation was evaluated by immunostaining with neural or glial specific markers, and the in vivo migration was assessed using immunohistology. Results The authors found that SF-hNSCs successfully engrafted into the chicken embryonic brain, which correlated with their ability to differentiate in vitro. NSCs grown at as low as 0.1% concentration of FBS failed to demonstrate the robust in vivo migration pattern but still preserved the capability to differentiate in vitro. Furthermore, NSCs generated in media containing a higher concentration of FBS (0.2%) lost both the in vivo engraftment and in vitro differentiation potential. Conclusions The present study suggests that marker expression and in vitro differentiation assays might not provide adequate information regarding the behavior of NSCs following their transplantation. The in vivo migration following injection into chicken embryonic brain may provide an important assay of the potency of NSCs.
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Du, Jian, Christian Agatemor, Christopher T. Saeui, Rahul Bhattacharya, Xiaofeng Jia, and Kevin J. Yarema. "Glycoengineering Human Neural and Adipose Stem Cells with Novel Thiol-Modified N-Acetylmannosamine (ManNAc) Analogs." Cells 10, no. 2 (February 12, 2021): 377. http://dx.doi.org/10.3390/cells10020377.
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This report describes novel thiol-modified N-acetylmannosamine (ManNAc) analogs that extend metabolic glycoengineering (MGE) applications of Ac5ManNTGc, a non-natural monosaccharide that metabolically installs the thio-glycolyl of sialic acid into human glycoconjugates. We previously found that Ac5ManNTGc elicited non-canonical activation of Wnt signaling in human embryoid body derived (hEBD) cells but only in the presence of a high affinity, chemically compatible scaffold. Our new analogs Ac5ManNTProp and Ac5ManNTBut overcome the requirement for a complementary scaffold by displaying thiol groups on longer, N-acyl linker arms, thereby presumably increasing their ability to interact and crosslink with surrounding thiols. These new analogs showed increased potency in human neural stem cells (hNSCs) and human adipose stem cells (hASCs). In the hNSCs, Ac5ManNTProp upregulated biochemical endpoints consistent with Wnt signaling in the absence of a thiol-reactive scaffold. In the hASCs, both Ac5ManNTProp and Ac5ManNTBut suppressed adipogenic differentiation, with Ac5ManNTBut providing a more potent response, and they did not interfere with differentiation to a glial lineage (Schwann cells). These results expand the horizon for using MGE in regenerative medicine by providing new tools (Ac5ManNTProp and Ac5ManNTBut) for manipulating human stem cells.
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Hosseini, Kimia, Emilia Lekholm, Aikeremu Ahemaiti, and Robert Fredriksson. "Differentiation of Human Embryonic Stem Cells into Neuron, Cholinergic, and Glial Cells." Stem Cells International 2020 (November 26, 2020): 1–9. http://dx.doi.org/10.1155/2020/8827874.
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Human embryonic stem cells (hESCs) are pluripotent cells, capable of differentiation into different cellular lineages given the opportunity. Derived from the inner cell mass of blastocysts in early embryonic development, the cell self-renewal ability makes them a great tool for regenerative medicine, and there are different protocols available for maintaining hESCs in their undifferentiated state. In addition, protocols for differentiation into functional human neural stem cells (hNSCs), which have the potential for further differentiation into various neural cell types, are available. However, many protocols are time-consuming and complex and do not always fit for purpose. In this study, we carefully combined, optimized, and developed protocols for differentiation of hESCs into adherent monolayer hNSCs over a short period of time, with the possibility of both expansion and freezing. Moreover, the method details further differentiation into neurons, cholinergic neurons, and glial cells in a simple, single step by step protocol. We performed immunocytochemistry, qPCR, and electrophysiology to examine the expression profile and characteristics of the cells to verify cell lineage. Using presented protocols, the creation of neuronal cultures, cholinergic neurons, and a mixed culture of astrocytes and oligodendrocytes can be completed within a three-week time period.
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Chung, Ming-Min, Christopher J. Nicol, Yi-Chuan Cheng, Kuan-Hung Lin, Yen-Lin Chen, Dee Pei, Chien-Hung Lin, et al. "Metformin activation of AMPK suppresses AGE-induced inflammatory response in hNSCs." Experimental Cell Research 352, no. 1 (March 2017): 75–83. http://dx.doi.org/10.1016/j.yexcr.2017.01.017.
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Zorniak, Michael, Paul A. Clark, and John S. Kuo. "Myelin-forming cell-specific cadherin-19 is a marker for minimally infiltrative glioblastoma stem-like cells." Journal of Neurosurgery 122, no. 1 (January 2015): 69–77. http://dx.doi.org/10.3171/2014.9.jns132373.
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OBJECT Glioblastoma stem-like cells (GSCs) exhibit stem-like properties, are highly efficient at forming tumor xenografts, and are resistant to many current therapies. Current molecular identifiers of GSCs are scarce and controversial. The authors describe differential cell-surface gene expression profiling to identify GSC-specific markers. METHODS Independent human GSC lines were isolated and maintained in standard neural stem cell (NSC) media and were validated for self-renewal, multipotent differentiation, and tumor initiation properties. Candidate upregulated GSCspecific plasma membrane markers were identified through differential Affymetrix U133 Plus 2.0 Array gene expression profiling of GSCs, human NSCs (hNSCs), normal brain tissue, and primary/recurrent glioblastoma multiforme samples. Results were validated by using comparative quantitative reverse transcription polymerase chain reaction and Western blot analysis of GSCs, hNSCs, normal human astrocytes, U87 glioma cell line, and patient-matched serum-cultured glioblastoma multiforme samples. RESULTS A candidate GSC-specific signature of 19 upregulated known and novel plasma membrane–associated genes was identified. Preferential upregulation of these plasma membrane–linked genes was validated by quantitative polymerase chain reaction. Cadherin-19 (CDH19) protein expression was enhanced in minimally infiltrative GSC lines. CONCLUSIONS Gene expression profiling of GSCs has shown CDH19 to be an exciting new target for drug development and study of GBM tumorigenesis.
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kim, su-young, Jung Sik Kim, and Chung Gyu Park. "Bystander immuno-modulatory effects of human neural stem cell line, HB1.F3, on lymphocyte proliferation induced by mitogens and alloantigens (81.9)." Journal of Immunology 178, no. 1_Supplement (April 1, 2007): S108—S109. http://dx.doi.org/10.4049/jimmunol.178.supp.81.9.
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Abstract A stable clonal cell line of human neural stem cells (NSCs), HB1.F3, has been shown therapeutic effect on acute stroke or intracerebral haemorrhage by the mechanisms of cell replacement and several bystander effects. To investigate the bystander immunomodulatory functions of HB1.F3 cells, we examined immunosuppressive effects of HB1.F3 on T cell effector functions in vitro. We found that heat-labile soluble factors from hNSCs culture supernatant are attributed to the inhibition of peripheral blood lymphocytes (PBLs) proliferation induced by mixed lymphocyte reaction (MLR) or phorbol myristate acetate (PMA)/ionomycin. In contrast to inhibitory effect of HB1.F3, they promoted cytokine secretion from PBLs including IFN-r, TNF-a, IL-10, IL-6 during mixed lymphocyte reaction by soluble factor dependant-manner. HB1.F3 cell line expressed TGF-beta and Trail mRNA, not FasL. we confirmed that the apoptosis induction of PBLs by HB1.F3 is one of the mechanisms of T cell proliferation inhibition during MLRs. In summary, HB1.F3 cells could suppress the T cell proliferation by induction of apoptosis and promote both inflammatory and immune suppressive cytokines. This study suggested that therapeutically effective hNSCs cell line on several stroke models might be due to the bystander immunomodulatory functions by the secretion of immunosuppressive soluble factors.
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Piltti, Katja, Martin Daffertshofer, and Brian Cummings. "Quantification of Human Neural Stem Cell Fate Using Volocity® 3D Image Analysis Software." Microscopy Today 20, no. 5 (September 2012): 34–36. http://dx.doi.org/10.1017/s1551929512000557.
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The promise of stem cell therapy offers hope for the treatment of many human diseases and injuries. Spinal cord and traumatic brain injuries can cause the loss of neurons and glial cells. These lost cells may be partially replaced by transplanting multipotent human neural stem cells (hNSCs), which can differentiate into specialized neural cell types. The potential for these remarkable cells to promote recovery of neural function has made them a strong focus of researchers in this field.
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Pelegri, Neus Gomila, Catherine A. Gorrie, and Jerran Santos. "Rat Hippocampal Neural Stem Cell Modulation Using PDGF, VEGF, PDGF/VEGF, and BDNF." Stem Cells International 2019 (March 18, 2019): 1–12. http://dx.doi.org/10.1155/2019/4978917.
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Neural stem cells have become the focus of many studies as they have the potential to differentiate into all three neural lineages. This may be utilised to develop new and novel ways to treat neurological conditions such as spinal cord and brain injuries, especially if the stem cells can be modulated in vivo without additional invasive surgical procedures. This research is aimed at investigating the effects of the growth factors vascular endothelial growth factor, platelet-derived growth factor, brain-derived neurotrophic factor, and vascular endothelial growth factor/platelet-derived growth factor on hippocampal-derived neural stem cells. Cell growth and differentiation were assessed using immunohistochemistry and glutaminase enzyme assay. Cells were cultured for 14 days and treated with different growth factors at two different concentrations 20 ng/mL and 100 ng/mL. At 2 weeks, cells were fixed, and immunohistochemistry was conducted to determine cellular differentiation using antibodies against GFAP, nestin, OSP, and NF200. The cell medium supernatant was also collected during treatment to determine glutaminase levels secreted by the cells as an indicator of neural differentiation. VEGF/PDGF at 100 ng/mL had the greatest influence on cellular proliferation of HNSC, which also stained positively for nestin, OSP, and NF200. In comparison, HNSC in other treatments had poorer cell health and adhesion. HNSC in all treatment groups displayed some differentiation markers and morphology, but this is most significant in the 100 ng/ml VEGF/PDGF treatment. VEGF/PDGF combination produced the optimal effect on the HNSCs inducing the differentiation pathway exhibiting oligodendrocytic and neuronal markers. This is a promising finding that should be further investigated in the brain and spinal cord injury.
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Liu, Shuang, Feng Yin, Mingming Zhao, Chunhui Zhou, Junlin Ren, Qiming Huang, Zhongming Zhao, Ramkrishna Mitra, Wenhong Fan, and Ming Fan. "The homing and inhibiting effects of hNSCs-BMP4 on human glioma stem cells." Oncotarget 7, no. 14 (February 18, 2016): 17920–31. http://dx.doi.org/10.18632/oncotarget.7472.
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Greilach, Scott A., Laura L. McIntyre, Jonathan Hasselmann, Shivashankar Othy, Quy Nguyen, Kai Kessenbrock, Michael D. Cahalan, Mathew Blurton-Jones, Thomas Lane, and Craig M. Walsh. "Human neural stem cells induce central nervous system specific regulatory T cells from the ex Treg pool and promote repair in models of multiple sclerosis." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 193.10. http://dx.doi.org/10.4049/jimmunol.202.supp.193.10.
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Abstract Multiple Sclerosis (MS) is a chronic inflammatory autoimmune disease affecting the central nervous system (CNS) and for which there is no cure. Current treatments focus on suppression of the immune system but fail to repair the resulting damage to the CNS. Neural stem cell (NSC) transplantation is a promising therapeutic strategy for treating neurodegenerative diseases through cell replacement and repair however it is unclear how these cells would mediate repair in MS. We report that human NSCs promote CNS specific T regulatory cells (Tregs) which activate endogenous repair pathways and promote remyelination in a murine model of MS. We observed remyelination, decreased inflammation and an increase in (CNS)-infiltrating CD4+CD25+FoxP3+ Tregs in EAE mice receiving an intra-spinal transplant of NSCs. Recovery was not a result of cell replacement, as NSCs underwent xenograft rejection, and was Treg dependent, as ablation of Tregs abrogated histopathological improvement. RAG2−/−2D2 (R2D2) mice, which bear a TCR repertoire restricted to myelin oligodendrocyte glycoprotein (MOG) and neurofilament, lack CD25+FoxP3+ Tregs under homeostatic conditions; however, upon exposure to MOG, R2D2 mice developed CD25+FoxP3+ Tregs in cervical lymph nodes and the spinal cord. hNSCs also promoted Tregs in vitro in co-cultures with wild type B6 and R2D2 splenocytes, but not with RAG2−/− OT-II+ splenocytes. Additionally, hNSC-Tregs also appear to derive from the exTreg pool suggesting both antigen specific expansion and antigen dependent maintenance of FOXP3 in CNS-specific Tregs. hNSC Tregs also have a unique expression profile and express transglutimase-2 which is implicated in oligodendrocyte dependent repair in the CNS.
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Park, Jun-Ook, Young Min Park, Woo-Jin Jeong, Yoo Seob Shin, Yong Tae Hong, Ik Joon Choi, Ji Won Kim, et al. "Survival Benefits From Surgery for Stage IVa Head and Neck Squamous Cell Carcinoma: A Multi-Institutional Analysis of 1,033 Cases." Clinical and Experimental Otorhinolaryngology 14, no. 2 (May 1, 2021): 225–34. http://dx.doi.org/10.21053/ceo.2020.01732.
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Objectives. Head and neck squamous cell carcinomas (HNSCs) are frequently diagnosed at the locoregional advanced stage (stage IVa), but controversy remains regarding whether stage IVa HSNCs should be treated with upfront surgery or definitive chemoradiation therapy (CRT). The purpose of this study was to compare overall survival (OS) and disease-free survival (DFS) in patients with stage IVa HNSC treated primarily by surgery with curative intent with/without (neo)adjuvant treatment (surgery group) versus those treated primarily with CRT (CRT group).Methods. We reviewed data of 1,033 patients with stage IVa HNSC treated with curative intent at 17 cancer centers between 2010 and 2016.Results. Among 1,033 patients, 765 (74.1%) received upfront surgery and 268 (25.9%) received CRT. The 5-year OS and DFS rates were 64.4% and 62.0% in the surgery group and 49.5% and 45.4% in the CRT group, respectively. In multivariate analyses, OS and DFS were better in the surgery group than in the CRT group (odds ratio [OR] for death, 0.762; 95% confidence interval [CI], 0.592–0.981; OR for recurrence, 0.628; 95% CI, 0.492–0.802). In subgroup analyses, the OS and DFS of patients with oropharyngeal cancer were better in the surgery group (OR for death, 0.548; 95% CI, 0.341–0.879; OR for recurrence, 0.598; 95% CI, 0.377–0.948). In the surgery group, patients with laryngeal cancer showed better OS (OR for death, 0.432; 95% CI, 0.211–0.882), while those with hypopharyngeal cancer DFS was improved (OR for recurrence, 0.506; 95% CI, 0.328–0.780).Conclusion. A survival benefit from surgery may be achieved even in patients with stage IVa HNSC, particularly those with oropharyngeal and laryngeal cancer. Surgery led to a reduction in the recurrence rate in patients with hypopharyngeal cancer.
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Emborg, M. E., S. Peng, J. Moirano, A. Ebert, M. Suzuki, B. Capowski, V. Joers, B. Roitberg, P. Aebischer, and C. Svendsen. "Survival of human neural stem cells (HNSCs) expressing GDNF in mptp-treated rhesus monkeys." Experimental Neurology 198, no. 2 (April 2006): 567. http://dx.doi.org/10.1016/j.expneurol.2006.02.039.
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Ropper, Alexander E., Xiang Zeng, Hariprakash Haragopal, Jamie E. Anderson, Zaid Aljuboori, Inbo Han, Muhammad Abd-El-Barr, et al. "Targeted Treatment of Experimental Spinal Cord Glioma With Dual Gene-Engineered Human Neural Stem Cells." Neurosurgery 79, no. 3 (December 14, 2015): 481–91. http://dx.doi.org/10.1227/neu.0000000000001174.
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Abstract BACKGROUND There are currently no satisfactory treatments or experimental models showing autonomic dysfunction for intramedullary spinal cord gliomas (ISCG). OBJECTIVE To develop a rat model of ISCG and investigate whether genetically engineered human neural stem cells (F3.hNSCs) could be developed into effective therapies for ISCG. METHODS Immunodeficient/Rowett Nude rats received C6 implantation of G55 human glioblastoma cells (10K/each). F3.hNSCs engineered to express either cytosine deaminase gene only (i.e., F3.CD) or dual genes of CD and thymidine kinase (i.e., F3.CD-TK) converted benign 5-fluorocytosine and ganciclovir into oncolytic 5-fluorouracil and ganciclovir-triphosphate, respectively. ISCG rats received injection of F3.CD-TK, F3.CD, or F3.CD-TK debris near the tumor epicenter 7 days after G55 seeding, followed with 5-FC (500 mg/kg/5 mL) and ganciclovir administrations (25 mg/kg/1 mL/day × 5/each repeat, intraperitoneal injection). Per humane standards for animals, loss of weight-bearing stepping in the hindlimb was used to determine post-tumor survival. Also evaluated were autonomic functions and tumor growth rate in vivo. RESULTS ISCG rats with F3.CD-TK treatment survived significantly longer (37.5 ± 4.78 days) than those receiving F3.CD (21.5 ± 1.75 days) or F3.CD-TK debris (19.3 ± 0.85 days; n = 4/group; P <.05, median rank test), with significantly improved autonomic function and reduced tumor growth rate. F3.DC-TK cells migrated diffusively into ISCG clusters to mediate oncolytic effect. CONCLUSION Dual gene-engineered human neural stem cell regimen markedly prolonged survival in a rat model that emulates somatomotor and autonomic dysfunctions of human cervical ISCG. F3.CD-TK may provide a novel approach to treating clinical ISCG.
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Moebius, Jeannette M., Darius Widera, Barbara Kaltschmidt, Christian Kaltschmidt, and Christoph Piechaczek. "Highly Efficient Neural Differentiation of Human Peripheral Blood Haematopoietic Stem Cells." Blood 108, no. 11 (November 16, 2006): 1678. http://dx.doi.org/10.1182/blood.v108.11.1678.1678.
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Abstract Neural stem cells are a potential source of cells for cell therapy of neurodegenerative diseases or drug screening. Ethical and practical considerations limit the application of neural stem cells derived from human embryonic stem cells or adult brain tissue. Therefore, alternative sources of adult human neural stem cells are of high interest for basic research as well as potential clinical use. These sources have to satisfy the demands of easy accession, rapid expansion in serum-free media and reliable induction to a neural fate. CD133 positive hematopoietic stem cells (HSCs) isolated from mobilized leukapheresis were cultured and expanded in the presence of epidermal growth factor (EGF) and fibroblast growth factor 2 (FGF-2/bFGF) in serum-free medium. After two weeks of culture, neurosphere formation was observed. Subsequent culture in serum-free, EGF and FGF-2 containing medium resulted in large numbers of CD133−, Nestin+ and Sox-2+ neural stem cells. Neural stem cells derived from HSCs (hNSCs) are highly proliferative and are able to migrate in response to chemotactic stimuli described to induce migration of neural stem cells. We used immunocytochemical techniques and PCR to assess neural differentiation. Adherence to poly-D-lysine/laminin and growth factor deprivation resulted in cells of neuronal morphology and high expression of neuronal differentiation markers. We furthermore show that after retinoic acid treatment neuronal induction was greatly enhanced with more than 90% of cells expressing neuronal differentiation markers as beta-III-tubulin and neurofilaments. In addition, hNSCs were able to differentiate into cells of the glial lineage as shown by expression of glial fibrillary acidic protein (GFAP). Our novel method provides nearly limitless numbers of neural stem cells from an easily accessible autologous adult human source, which could be used as a starting point for further experimental studies and potential therapeutic use.
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Xie, Chong, Kan Wang, Jing Peng, Xianguo Jiang, Shuting Pan, Liping Wang, Yifan Wu, and Yangtai Guan. "Efficacy and safety of human-derived neural stem cell in patients with ischaemic stroke: study protocol for a randomised controlled trial." BMJ Open 12, no. 11 (November 2022): e055108. http://dx.doi.org/10.1136/bmjopen-2021-055108.
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IntroductionStroke is the most common cause of neurological disability in adults worldwide. Neural stem cell (NSC) transplantation has shown promising results as a treatment for stroke in animal experiments. The pilot investigation of stem cells in stroke phase 1 and phase 2 trials showed that transplantation of the highest dose (20 million cells) was well tolerated. Preliminary clinical benefits have also been observed. However, the trials were open-label and had a small sample size. Furthermore, human NSCs (hNSCs) were intracerebrally implanted, and some serious adverse events were considered to be related to the surgical procedure. Therefore, we plan to conduct a double-blinded, randomised controlled trial to test the safety and efficacy of intranasal injection of hNSCs.Methods and analysisThis single-centre, randomised, double-blinded, parallel-controlled trial will be conducted in China. Sixty patients with ischaemic stroke who met the qualification criteria will be randomly divided into two groups: the NSCs and control groups. All participants will receive intranasal administration of hNSCs or placebo for 4 consecutive weeks. Patients will be followed up at baseline and at 4, 12, 24 and 48 weeks after intervention. The primary outcome is the National Institutes of Health Stroke Scale score (4, 12, 24 weeks after intervention). Secondary outcomes include the modified Rankin scale, Barthel index, Mini-Mental State Examination score (4, 12, 24 weeks after intervention) and cranial MRI changes (24 and 48 weeks after intervention). All adverse events will be recorded during the study period.Ethics and disseminationThe study protocol was approved by the Ethics Committee of Ren Ji Hospital (2018-009). All subjects will provide informed consent. The results will be accessible in peer-reviewed publications and will be presented at academic conferences.Trial registrationChiCTR1900022741; Chinese Clinical Trial Registry.
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Bakhshinyan, David, Ashley A. Adile, Chitra Venugopal, Kevin Brown, Katherine Chan, Maleeha A. Qazi, Chirayu Chokshi, et al. "EMBR-22. RATIONAL DEVELOPMENT OF SYNERGISTIC THERAPIES ALONGSIDE BMI1 INHIBITION FOR GROUP 3 MEDULLOBLASTOMA." Neuro-Oncology 23, Supplement_1 (June 1, 2021): i10. http://dx.doi.org/10.1093/neuonc/noab090.040.
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Abstract Medulloblastoma (MB) is the most common pediatric brain tumor. Of its four distinct molecular subgroups, Group 3 MBs are associated with increased risk of recurrence, metastasis and overall poor patient outcome. In recent years, small molecule inhibitors targeting BMI1 have shown to be efficacious against several types of malignant tumors including pediatric MB. Although in vivo studies provide a promising proof-of-concept for the therapeutic targeting of BMI1 in Group 3 MB, mice that receive treatment eventually succumb to their disease. These results suggest that additional mechanisms may underlie the maintenance of MB and underscores the main obstacle in treating a constantly evolving tumor. After initial preclinical validation of BMI1 inhibitor PTC-596, DNA barcoding clonal tracking technology was leveraged to profile in vivo clonal dynamics of Group 3 MB in response to the established chemoradiotherapy regimen alone and in combination with PTC-596. Comparison of clonal composition of the tumors extracted from the brains and spines post-treatment revealed the persistence of a small number of clones with the ability to escape therapy and drive subsequent tumor expansion. In order to better understand molecular susceptibilities of MB cells post BMI1 inhibition, we undertook an in vitro genome-wide CRISPR/Cas9 screening to identify context-specific MB regulatory pathways to be synergistically targeted along with BMI1. By comparing the results of the in vitro genome wide CRISPR/Cas9 screen to the essential genes in human neural stem cells (hNSCs), we identified several context specific regulators of mTOR, AKT and PLK1 pathways. The combined treatment alongside PTC-596 has demonstrated synergistic efficacy against MB cells with minimal toxicity to hNSCs in vitro and is currently being evaluated in preclinical studies. This study provides the foundation for clinical validation of small-molecule inhibitors synergistic with PTC-596 to improve the durability of remissions and extend survival of patients with treatment-refractory Group 3 MB.
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Moon, Haena, Seong Gak Jeon, Jin-il Kim, Hyeon soo Kim, Sangho Lee, Dongok Kim, Seungjoon Park, Minho Moon, and Hyunju Chung. "Pharmacological Stimulation of Nurr1 Promotes Cell Cycle Progression in Adult Hippocampal Neural Stem Cells." International Journal of Molecular Sciences 21, no. 1 (December 18, 2019): 4. http://dx.doi.org/10.3390/ijms21010004.
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Nuclear receptor related-1 (Nurr1) protein performs a crucial role in hippocampal neural stem cell (hNSC) development as well as cognitive functions. We previously demonstrated that the pharmacological stimulation of Nurr1 by amodiaquine (AQ) promotes spatial memory by enhancing adult hippocampal neurogenesis. However, the role of Nurr1 in the cell cycle regulation of the adult hippocampus has not been investigated. This study aimed to examine changes in the cell cycle-related molecules involved in adult hippocampal neurogenesis induced by Nurr1 pharmacological stimulation. Fluorescence-activated cell sorting (FACS) analysis showed that AQ improved the progression of cell cycle from G0/G1 to S phase in a dose-dependent manner, and MEK1 or PI3K inhibitors attenuated this progression. In addition, AQ treatment increased the expression of cell proliferation markers MCM5 and PCNA, and transcription factor E2F1. Furthermore, pharmacological stimulation of Nurr1 by AQ increased the expression levels of positive cell cycle regulators such as cyclin A and cyclin-dependent kinases (CDK) 2. In contrast, levels of CDK inhibitors p27KIP1 and p57KIP2 were reduced upon treatment with AQ. Similar to the in vitro results, RT-qPCR analysis of AQ-administered mice brains revealed an increase in the levels of markers of cell cycle progression, PCNA, MCM5, and Cdc25a. Finally, AQ administration resulted in decreased p27KIP1 and increased CDK2 levels in the dentate gyrus of the mouse hippocampus, as quantified immunohistochemically. Our results demonstrate that the pharmacological stimulation of Nurr1 in adult hNSCs by AQ promotes the cell cycle by modulating cell cycle-related molecules.
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Kandasamy, Majury, Lars Roll, Daniel Langenstroth, Oliver Brüstle, and Andreas Faissner. "Glycoconjugates reveal diversity of human neural stem cells (hNSCs) derived from human induced pluripotent stem cells (hiPSCs)." Cell and Tissue Research 368, no. 3 (March 15, 2017): 531–49. http://dx.doi.org/10.1007/s00441-017-2594-z.
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Ahn, J., T. Mirza, A. Hicks, and P. Ameerally. "An audit of infection rates in head and neck skin cancer surgery (HNSCS) in different clinical settings." British Journal of Oral and Maxillofacial Surgery 49 (June 2011): S22—S23. http://dx.doi.org/10.1016/j.bjoms.2011.04.058.
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Kondoh, Nobuo, and Masako Mizuno-Kamiya. "The Role of Immune Modulatory Cytokines in the Tumor Microenvironments of Head and Neck Squamous Cell Carcinomas." Cancers 14, no. 12 (June 11, 2022): 2884. http://dx.doi.org/10.3390/cancers14122884.
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HNSCCs are the major progressive malignancy of the upper digestive and respiratory organs. Malignant phenotypes of HNSCCs are regulated by the pro- and anti-tumoral activities of the immune modulatory cytokines associated with TMEs, i.e., a representative pro-inflammatory cytokine, interferon (IFN)-γ, plays a role as an anti-tumor regulator against HNSCCs; however, IFN-γ also drives programmed death-ligand (PD-L) 1 expression to promote cancer stem cells. Interleukin (IL)-2 promotes the cytotoxic activity of T cells and natural killer cells; however, endogenous IL-2 can promote regulatory T cells (Tregs), resulting in the protection of HNSCCs. In this report, we first classified and mentioned the immune modulatory aspects of pro-inflammatory cytokines, pro-/anti-inflammatory cytokines, and anti-inflammatory cytokines upon HNSCC phenotypes. In the TME of HNSCCs, pro-tumoral immune modulation is mediated by stromal cells, including CAFs, MDSCs, pDCs, and TAMs. Therefore, we evaluated the functions of cytokines and chemokines that mediate the crosstalk between tumor cells and stromal cells. In HNSCCs, the status of lymph node metastasis is an important hallmark of a worse prognosis. We therefore evaluated the possibility of chemokines mediating lymph node metastases in HNSCC patients. We also mention therapeutic approaches using anti-tumoral cytokines or immunotherapies that target cytokines, chemokines, or signal molecules essential for the immune evasion of HNSCCs. We finally discuss modulation by HPV infection upon HNSCC phenotypes, as well as the prognostic significance of serum cytokine levels in HNSCC patients.
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Ma and Suh. "Cost-Effective Cosmetic-Grade Hyaluronan Hydrogels for ReNcell VM Human Neural Stem Cell Culture." Biomolecules 9, no. 10 (September 20, 2019): 515. http://dx.doi.org/10.3390/biom9100515.
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Hyaluronic acid (HA) is a polysaccharide polymer frequently used as a starting material to fabricate hydrogels, especially for recapitulating the brain’s extracellular matrix (ECM) for in vitro neural stem cell (NSC) cultures. Here, we report the successful synthesis of a methacrylated HA (MeHA) polymer from an inexpensive cosmetic-grade hyaluronan starting material. The MeHA polymers synthesized from cosmetic-grade HA yielded similar chemical purity to those from pharmaceutical/research-grade HA reported in the literature. Crosslinked MeHA (x-MeHA) hydrogels were formed using radical polymerization which resulted in mechanical properties matching previously reported mechanical property ranges for enhanced neuronal differentiation of NSCs. We assessed cellular adhesion, spreading, proliferation, and stiffness-dependent neuronal differentiation properties of ReNcell VM human neural stem cells (hNSCs) and compared our results to studies reported in the literature (that utilized non-human and human pluripotent cell-derived NSCs).