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NF-kB in Stem Cells and the Nervous System: From Embryonal Development to Adulthood

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A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Stem Cells".

Deadline for manuscript submissions: closed (1 October 2021) | Viewed by 22696

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Special Issue Editor

Prof. Dr. Barbara Kaltschmidt

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Guest Editor

Department of Cell Biology, AG Molecular Neurobiology, Bielefeld University, Universitätsstrasse 25, 33615 Bielefeld, Germany
Interests: stem cells; neural crest; transcription factor NF-kB; neuroprotection and neurodegeneration; cancer stem cells; bone regeneration; inflammation; sex-specific cell biology

Special Issue Information

Dear Colleagues,

Nuclear factor kappa B (NF-kB) is an inducible transcription factor discovered nearly thirty years ago in the lab of David Baltimore. Since then, NF-kB has been found to play key functions in development, inflammation, cell proliferation, the immune system, as well as in the nervous system.

As a novel topic in recent years, the role of NF-kB in stem cells has been investigated. This research included embryonic stem cells and their laboratory-made counterparts (induced pluripotent stem cells) followed by tissue resident adult stem cells. The aim of this Special Issue is to review the contribution of NF-kB from the inner cell mass of the blastula (embryonic stem cells) to the development of the neural crest and the nervous system.

Discussions of human and animal model systems are very welcome.

Prof. Dr. Barbara Kaltschmidt
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

Transcription factor NF-kB
Stem cells
Nervous system
Development
Cell fate

Published Papers (6 papers)

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Research

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27 pages, 8512 KiB

Open AccessArticle

IKK2/NF-κB Activation in Astrocytes Reduces amyloid β Deposition: A Process Associated with Specific Microglia Polarization

by Shu Yang, Alexander Magnutzki, Najwa Ouali Alami, Michael Lattke, Tabea Melissa Hein, Judith Stefanie Scheller, Carsten Kröger, Franz Oswald, Deniz Yilmazer-Hanke, Thomas Wirth and Bernd Baumann

Cells 2021, 10(10), 2669; https://doi.org/10.3390/cells10102669 - 06 Oct 2021

Cited by 13 | Viewed by 3895

Abstract

Alzheimer’s disease (AD) is a common neurodegenerative disease that is accompanied by pronounced neuroinflammatory responses mainly characterized by marked microgliosis and astrogliosis. However, it remains open as to how different aspects of astrocytic and microglial activation affect disease progression. Previously, we found that microglia expansion in the spinal cord, initiated by IKK2/NF-κB activation in astrocytes, exhibits stage-dependent beneficial effects on the progression of amyotrophic lateral sclerosis. Here, we investigated the impact of NF-κB-initiated neuroinflammation on AD pathogenesis using the APP23 mouse model of AD in combination with conditional activation of IKK2/NF-κB signaling in astrocytes. We show that NF-κB activation in astrocytes triggers a distinct neuroinflammatory response characterized by striking astrogliosis as well as prominent microglial reactivity. Immunohistochemistry and Congo red staining revealed an overall reduction in the size and number of amyloid plaques in the cerebral cortex and hippocampus. Interestingly, isolated primary astrocytes and microglia cells exhibit specific marker gene profiles which, in the case of microglia, point to an enhanced plaque clearance capacity. In contrast, direct IKK2/NF-κB activation in microglia results in a pro-inflammatory polarization program. Our findings suggest that IKK2/NF-κB signaling in astrocytes may activate paracrine mechanisms acting on microglia function but also on APP processing in neurons. Full article

(This article belongs to the Special Issue NF-kB in Stem Cells and the Nervous System: From Embryonal Development to Adulthood)

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25 pages, 11147 KiB

Open AccessArticle

Novel Primary Human Cancer Stem-Like Cell Populations from Non-Small Cell Lung Cancer: Inhibition of Cell Survival by Targeting NF-κB and MYC Signaling

by Beatrice A. Windmöller, Morris Beshay, Laureen P. Helweg, Clara Flottmann, Miriam Beermann, Christine Förster, Ludwig Wilkens, Johannes F. W. Greiner, Christian Kaltschmidt and Barbara Kaltschmidt

Cells 2021, 10(5), 1024; https://doi.org/10.3390/cells10051024 - 27 Apr 2021

Cited by 12 | Viewed by 2890

Abstract

There is growing evidence that cancer stem cells (CSCs), a small subpopulation of self-renewal cancer cells, are responsible for tumor growth, treatment resistance, and cancer relapse and are thus of enormous clinical interest. Here, we aimed to isolate new CSC-like cells derived from human primary non-small cell lung cancer (NSCLC) specimens and to analyze the influence of different inhibitors of NF-κB and MYC signaling on cell survival. CSC-like cells were established from three squamous cell carcinomas (SCC) and three adenocarcinomas (AC) of the lung and were shown to express common CSC markers such as Prominin-1, CD44-antigen, and Nestin. Further, cells gave rise to spherical cancer organoids. Inhibition of MYC and NF-κB signaling using KJ-Pyr-9, dexamethasone, and pyrrolidinedithiocarbamate resulted in significant reductions in cell survival for SCC- and AC-derived cells. However, inhibition of the protein–protein interaction of MYC/NMYC proto-oncogenes with Myc-associated factor X (MAX) using KJ-Pyr-9 revealed the most promising survival-decreasing effects. Next to the establishment of six novel in vitro models for studying NSCLC-derived CSC-like populations, the presented investigations might provide new insights into potential novel therapies targeting NF-κB/MYC to improve clinical outcomes in NSCLC patients. Nevertheless, the full picture of downstream signaling still remains elusive. Full article

(This article belongs to the Special Issue NF-kB in Stem Cells and the Nervous System: From Embryonal Development to Adulthood)

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18 pages, 3187 KiB

Open AccessArticle

NF-κB and TNF Affect the Astrocytic Differentiation from Neural Stem Cells

by Cindy Birck, Aurélien Ginolhac, Maria Angeliki S. Pavlou, Alessandro Michelucci, Paul Heuschling and Luc Grandbarbe

Cells 2021, 10(4), 840; https://doi.org/10.3390/cells10040840 - 08 Apr 2021

Cited by 10 | Viewed by 3129

Abstract

The NF-κB signaling pathway is crucial during development and inflammatory processes. We have previously shown that NF-κB activation induces dedifferentiation of astrocytes into neural progenitor cells (NPCs). Here, we provide evidence that the NF-κB pathway plays also a fundamental role during the differentiation of NPCs into astrocytes. First, we show that the NF-κB pathway is essential to initiate astrocytic differentiation as its early inhibition induces NPC apoptosis and impedes their differentiation. Second, we demonstrate that persistent NF-κB activation affects NPC-derived astrocyte differentiation. Tumor necrosis factor (TNF)-treated NPCs show NF-κB activation, maintain their multipotential and proliferation properties, display persistent expression of immature markers and inhibit astrocyte markers. Third, we analyze the effect of NF-κB activation on the main known astrocytic differentiation pathways, such as NOTCH and JAK-STAT. Our findings suggest that the NF-κB pathway plays a dual fundamental role during NPC differentiation into astrocytes: it promotes astrocyte specification, but its persistent activation impedes their differentiation. Full article

(This article belongs to the Special Issue NF-kB in Stem Cells and the Nervous System: From Embryonal Development to Adulthood)

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Review

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17 pages, 1857 KiB

Open AccessFeature PaperReview

The Transcription Factor NF-κB in Stem Cells and Development

by Christian Kaltschmidt, Johannes F. W. Greiner and Barbara Kaltschmidt

Cells 2021, 10(8), 2042; https://doi.org/10.3390/cells10082042 - 10 Aug 2021

Cited by 51 | Viewed by 4720

Abstract

NF-κB (nuclear factor kappa B) belongs to a family of transcription factors known to regulate a broad range of processes such as immune cell function, proliferation and cancer, neuroprotection, and long-term memory. Upcoming fields of NF-κB research include its role in stem cells and developmental processes. In the present review, we discuss one role of NF-κB in development in Drosophila, Xenopus, mice, and humans in accordance with the concept of evo-devo (evolutionary developmental biology). REL domain-containing proteins of the NF-κB family are evolutionarily conserved among these species. In addition, we summarize cellular phenotypes such as defective B- and T-cell compartments related to genetic NF-κB defects detected among different species. While NF-κB proteins are present in nearly all differentiated cell types, mouse and human embryonic stem cells do not contain NF-κB proteins, potentially due to miRNA-dependent inhibition. However, the mesodermal and neuroectodermal differentiation of mouse and human embryonic stem cells is hampered upon the repression of NF-κB. We further discuss NF-κB as a crucial regulator of differentiation in adult stem cells such as neural crest-derived and mesenchymal stem cells. In particular, c-REL seems to be important for neuronal differentiation and the neuroprotection of human adult stem cells, while RELA plays a crucial role in osteogenic and mesodermal differentiation. Full article

(This article belongs to the Special Issue NF-kB in Stem Cells and the Nervous System: From Embryonal Development to Adulthood)

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Graphical abstract

14 pages, 1127 KiB

Open AccessReview

Regulation of Transcription Factor NF-κB in Its Natural Habitat: The Nucleus

by Susanne Bacher, Johanna Meier-Soelch, Michael Kracht and M. Lienhard Schmitz

Cells 2021, 10(4), 753; https://doi.org/10.3390/cells10040753 - 29 Mar 2021

Cited by 13 | Viewed by 3026

Abstract

Activation of the transcription factor NF-κB elicits an individually tailored transcriptional response in order to meet the particular requirements of specific cell types, tissues, or organs. Control of the induction kinetics, amplitude, and termination of gene expression involves multiple layers of NF-κB regulation in the nucleus. Here we discuss some recent advances in our understanding of the mutual relations between NF-κB and chromatin regulators also in the context of different levels of genome organization. Changes in the 3D folding of the genome, as they occur during senescence or in cancer cells, can causally contribute to sustained increases in NF-κB activity. We also highlight the participation of NF-κB in the formation of hierarchically organized super enhancers, which enable the coordinated expression of co-regulated sets of NF-κB target genes. The identification of mechanisms allowing the specific regulation of NF-κB target gene clusters could potentially enable targeted therapeutic interventions, allowing selective interference with subsets of the NF-κB response without a complete inactivation of this key signaling system. Full article

(This article belongs to the Special Issue NF-kB in Stem Cells and the Nervous System: From Embryonal Development to Adulthood)

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16 pages, 765 KiB

Open AccessReview

Multi-Level Regulatory Interactions between NF-κB and the Pluripotency Factor Lin28

by William T. Mills IV, Noor N. Nassar, Deepa Ravindra, Xinbei Li and Mollie K. Meffert

Cells 2020, 9(12), 2710; https://doi.org/10.3390/cells9122710 - 17 Dec 2020

Cited by 6 | Viewed by 4154

Abstract

An appreciation for the complex interactions between the NF-κB transcription factor and the Lin28 RNA binding protein/let-7 microRNA pathways has grown substantially over the past decade. Both the NF-κB and Lin28/let-7 pathways are master regulators impacting cell survival, growth and proliferation, and an understanding of how interfaces between these pathways participate in governing pluripotency, progenitor differentiation, and neuroplastic responses remains an emerging area of research. In this review, we provide a concise summary of the respective pathways and focus on the function of signaling interactions at both the transcriptional and post-transcriptional levels. Regulatory loops capable of providing both reinforcing and extinguishing feedback have been described. We highlight convergent findings in disparate biological systems and indicate future directions for investigation. Full article

(This article belongs to the Special Issue NF-kB in Stem Cells and the Nervous System: From Embryonal Development to Adulthood)

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