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A Matter of Choice: Inhibition of c-Rel Shifts Neuronal to Oligodendroglial Fate in Human Stem Cells
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...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226153/ https://www.ncbi.nlm.nih.gov/pubmed/32331232 http://dx.doi.org/10.3390/cells9041037 |
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author | Ruiz-Perera, Lucia Mercedes Greiner, Johannes Friedrich Wilhelm Kaltschmidt, Christian Kaltschmidt, Barbara |
author_facet | Ruiz-Perera, Lucia Mercedes Greiner, Johannes Friedrich Wilhelm Kaltschmidt, Christian Kaltschmidt, Barbara |
author_sort | Ruiz-Perera, Lucia Mercedes |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-7226153 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-72261532020-05-18 A Matter of Choice: Inhibition of c-Rel Shifts Neuronal to Oligodendroglial Fate in Human Stem Cells Ruiz-Perera, Lucia Mercedes Greiner, Johannes Friedrich Wilhelm Kaltschmidt, Christian Kaltschmidt, Barbara Cells Article 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. MDPI 2020-04-22 /pmc/articles/PMC7226153/ /pubmed/32331232 http://dx.doi.org/10.3390/cells9041037 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Ruiz-Perera, Lucia Mercedes Greiner, Johannes Friedrich Wilhelm Kaltschmidt, Christian Kaltschmidt, Barbara A Matter of Choice: Inhibition of c-Rel Shifts Neuronal to Oligodendroglial Fate in Human Stem Cells |
title | A Matter of Choice: Inhibition of c-Rel Shifts Neuronal to Oligodendroglial Fate in Human Stem Cells |
title_full | A Matter of Choice: Inhibition of c-Rel Shifts Neuronal to Oligodendroglial Fate in Human Stem Cells |
title_fullStr | A Matter of Choice: Inhibition of c-Rel Shifts Neuronal to Oligodendroglial Fate in Human Stem Cells |
title_full_unstemmed | A Matter of Choice: Inhibition of c-Rel Shifts Neuronal to Oligodendroglial Fate in Human Stem Cells |
title_short | A Matter of Choice: Inhibition of c-Rel Shifts Neuronal to Oligodendroglial Fate in Human Stem Cells |
title_sort | matter of choice: inhibition of c-rel shifts neuronal to oligodendroglial fate in human stem cells |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226153/ https://www.ncbi.nlm.nih.gov/pubmed/32331232 http://dx.doi.org/10.3390/cells9041037 |
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