Experimental and clinical factors influencing long-term stable in vitro expansion of multipotent neural cells from human adult temporal lobes

Joo, Kyeung Min; Kang, Bong Gu; Yeon, Je Young; Cho, Yu Jin; An, Jae Yeol; Song, Hyeon Suk; Won, Jun Ho; Kim, Sang Jeong; Hong, Seung Chyul; Nam, Do Hyun

doi:10.1016/j.expneurol.2012.11.021

Cited by 18 publications

(46 citation statements)

References 47 publications

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“…To confirm the stem cell characteristics of rfNSCs, the expression of NSC markers such as Nestin, Sox2, and Musashi1 was compared by RT-PCR ( Fig 1B ) between the neurosphere culture at P1 and adherent culture at P4. The results showed that the expression of NSC markers was similar between both culture methods which is consistent with our prior research [ 26 ]. Differentiation was carried out in the complete medium without EGF and bFGF for 2 weeks, which resulted in the decreased expression of NSC markers such as Nestin and increased expression of differentiated neural cell markers such as NeuN (neuron), Olig2 (oligodendrocyte), and GFAP (astrocyte) ( Fig 1C ).…”

Section: Resultssupporting

confidence: 91%

The Synergistic Local Immunosuppressive Effects of Neural Stem Cells Expressing Indoleamine 2,3-Dioxygenase (IDO) in an Experimental Autoimmune Encephalomyelitis (EAE) Animal Model

Lee

et al. 2015

PLoS ONE

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Neurodegenerative diseases provoke robust immunological reactions in the central nervous system (CNS), which further deteriorate the neural tissue damage. We hypothesized that the expression levels of indoleamine 2,3-dioxygenase (IDO), an enzyme that has potent immune suppressive activities, in neural stem cells (NSCs) would have synergistic therapeutic effects against neurodegenerative diseases, since NSCs themselves have low IDO expression. In this study, the synergistic immune suppressive effects of rat fetal NSCs expressing IDO (rfNSCs-IDO) were validated by mixed leukocyte reaction (MLR) in vitro and an experimental autoimmune encephalomyelitis (EAE) animal model in vivo. rfNSCs-IDO showed significantly more suppressive effects on T cell proliferation in the MLR compared to control rfNSCs (rfNSCs-Cont). Importantly, IDO inhibition using 1-methyl-DL-tryptophan (1-MT), an IDO inhibitor, reversed the synergistic effects, confirming IDO-specific effects in rfNSCs-IDO. In the EAE animal model, systemic rfNSCs-IDO injections resulted in significant local immune suppression in the cervical lymph nodes and CNS, evidenced by a reduction in the number of activated T lymphocytes and an increase in regulatory T cell numbers, which induced significantly fewer clinical symptoms and faster recovery. In contrast, rfNSCs-Cont failed to reduce symptoms in the EAE animal models, although they showed local immune suppression, which was significantly less than that in rfNSCs-IDO. Taken together, IDO expression in NSCs synergistically potentiates the immune suppression activities of NSCs and could be applicable for the development of therapeutic modalities against various neurodegenerative diseases.

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Section: Resultssupporting

confidence: 91%

The Synergistic Local Immunosuppressive Effects of Neural Stem Cells Expressing Indoleamine 2,3-Dioxygenase (IDO) in an Experimental Autoimmune Encephalomyelitis (EAE) Animal Model

Lee

et al. 2015

PLoS ONE

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“…To overcome this situation, neuro-regeneration with stem cells is emerging as a promising treatment because stem cells have differentiation potential into various cells to replace damaged neural tissue [ 1 , 2 ]. Stem cell sources, such as bone marrow, adipose tissue, teeth, and placenta, can make neural cells [ 4 – 7 ]. However, their differentiation capacities remain controversial [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

Sensitive Tumorigenic Potential Evaluation of Adult Human Multipotent Neural Cells Immortalized by hTERT Gene Transduction

et al. 2016

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Stem cells and therapeutic genes are emerging as a new therapeutic approach to treat various neurodegenerative diseases with few effective treatment options. However, potential formation of tumors by stem cells has hampered their clinical application. Moreover, adequate preclinical platforms to precisely test tumorigenic potential of stem cells are controversial. In this study, we compared the sensitivity of various animal models for in vivo stem cell tumorigenicity testing to identify the most sensitive platform. Then, tumorigenic potential of adult human multipotent neural cells (ahMNCs) immortalized by the human telomerase reverse transcriptase (hTERT) gene was examined as a stem cell model with therapeutic genes. When human glioblastoma (GBM) cells were injected into adult (4–6-week-old) Balb/c-nu, adult NOD/SCID, adult NOG, or neonate (1–2-week-old) NOG mice, the neonate NOG mice showed significantly faster tumorigenesis than that of the other groups regardless of intracranial or subcutaneous injection route. Two kinds of ahMNCs (682TL and 779TL) were primary cultured from surgical samples of patients with temporal lobe epilepsy. Although the ahMNCs were immortalized by lentiviral hTERT gene delivery (hTERT-682TL and hTERT-779TL), they did not form any detectable masses, even in the most sensitive neonate NOG mouse platform. Moreover, the hTERT-ahMNCs had no gross chromosomal abnormalities on a karyotype analysis. Taken together, our data suggest that neonate NOG mice could be a sensitive animal platform to test tumorigenic potential of stem cell therapeutics and that ahMNCs could be a genetically stable stem cell source with little tumorigenic activity to develop regenerative treatments for neurodegenerative diseases.

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“…We have previously established the culture method for human multipotent neural cells, as well as the sphere culture method for retaining the stemness of GBM cells [ 21 ]. Surgical samples from temporal lobe epilepsy patients were cultured under the neurosphere culture conditions without serum.…”

Section: Resultsmentioning

confidence: 99%

Glioblastoma specific antigens, GD2 and CD90, are not involved in cancer stemness

Woo

et al. 2015

Anat Cell Biol

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Glioblastoma multiforme (GBM) is the most malignant World Health Organization grade IV brain tumor. GBM patients have a poor prognosis because of its resistance to standard therapies, such as chemotherapy and radiation. Since stem-like cells have been associated with the treatment resistance of GBM, novel therapies targeting the cancer stem cell (CSC) population is critically required. However, GBM CSCs share molecular and functional characteristics with normal neural stem cells (NSCs). To elucidate differential therapeutic targets of GBM CSCs, we compared surface markers of GBM CSCs with adult human NSCs and found that GD2 and CD90 were specifically overexpressed in GBM CSCs. We further tested whether the GBM CSC specific markers are associated with the cancer stemness using primarily cultured patient-derived GBM cells. However, results consistently indicated that GBM cells with or without GD2 and CD90 had similar in vitro sphere formation capacity, a functional characteristics of CSCs. Therefore, GD2 and CD90, GBM specific surface markers, might not be used as specific therapeutic targets for GBM CSCs, although they could have other clinical utilities.

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Experimental and clinical factors influencing long-term stable in vitro expansion of multipotent neural cells from human adult temporal lobes

Cited by 18 publications

References 47 publications

The Synergistic Local Immunosuppressive Effects of Neural Stem Cells Expressing Indoleamine 2,3-Dioxygenase (IDO) in an Experimental Autoimmune Encephalomyelitis (EAE) Animal Model

The Synergistic Local Immunosuppressive Effects of Neural Stem Cells Expressing Indoleamine 2,3-Dioxygenase (IDO) in an Experimental Autoimmune Encephalomyelitis (EAE) Animal Model

Sensitive Tumorigenic Potential Evaluation of Adult Human Multipotent Neural Cells Immortalized by hTERT Gene Transduction

Glioblastoma specific antigens, GD2 and CD90, are not involved in cancer stemness

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