scholarly journals A Matter of Choice: Inhibition of c-Rel Shifts Neuronal to Oligodendroglial Fate in Human Stem Cells

Cells ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 1037 ◽  
Author(s):  
Lucia Mercedes Ruiz-Perera ◽  
Johannes Friedrich Wilhelm Greiner ◽  
Christian Kaltschmidt ◽  
Barbara Kaltschmidt
Keyword(s):  
Stem Cells ◽  
Molecular Mechanisms ◽  
Neuronal Development ◽  
Therapeutic Potential ◽  
Ex Vivo ◽  
Transcript Level ◽  
Human Stem Cells ◽  
Human Neural Stem Cells ◽  
Essential Function

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.

NF-κB-c-REL impairment drives human stem cells into the oligodendroglial fate

2019 ◽  
Author(s):  
Lucia M Ruiz-Perera ◽  
Johannes FW Greiner ◽  
Christian Kaltschmidt ◽  
Barbara Kaltschmidt
Keyword(s):  
Stem Cells ◽  
Neuronal Differentiation ◽  
Molecular Mechanisms ◽  
Neuronal Development ◽  
System Development ◽  
Nervous System Development ◽  
Human Stem Cells ◽  
Human Neural Stem Cells ◽  
Transcription Factor Nuclear Factor

AbstractMolecular mechanisms underlying fate decisions of human neural stem cells (NSCs) between neurogenesis and gliogenesis are critical during neuronal development and progression of neurodegenerative diseases. Despite its crucial role in murine nervous system development, the potential role of the transcription factor nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-κB) in fate shifts of human stem cells is poorly understood.Facing this challenge, we demonstrate here that NF-κB-c-REL drives glutamatergic differentiation of adult human stem cells, while its impairment results in a shift towards the oligodendroglial fate. We particularly observed an opposing balance switch from NF-κB-RELB/p52 to NF-κB-c-REL during early neuronal differentiation of NSCs originating from neural crest-derived stem cells. Exposure of differentiating human NSCs to the c-REL inhibiting approved drug pentoxifylline (PTXF) resulted in elevated levels of cell death and significantly decreased amounts of NF200+/VGLUT2+ neurons. PTXF-mediated inhibition of c-REL further drove human NSCs into the oligodendrocyte fate, as demonstrated by a complete switch to OLIG2+/O4+ oligodendrocytes, which also showed PDGFRα, NG2 and MBP transcripts.In summary, we present here a novel human cellular model of neuronal differentiation with an essential role of NF-κB-c-REL in fate choice between neurogenesis and oligodendrogenesis potentially relevant for multiple sclerosis and schizophrenia.

scholarly journals MARTs and MARylation in the Cytosol: Biological Functions, Mechanisms of Action, and Therapeutic Potential

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 313
Author(s):  
Sridevi Challa ◽  
MiKayla S. Stokes ◽  
W. Lee Kraus
Keyword(s):  
Stress Responses ◽  
Molecular Mechanisms ◽  
Neuronal Development ◽  
New Technologies ◽  
Therapeutic Potential ◽  
Structural Features ◽  
Cellular Transport ◽  
Biological Functions ◽  
Post Translational Modification

Mono(ADP-ribosyl)ation (MARylation) is a regulatory post-translational modification of proteins that controls their functions through a variety of mechanisms. MARylation is catalyzed by mono(ADP-ribosyl) transferase (MART) enzymes, a subclass of the poly(ADP-ribosyl) polymerase (PARP) family of enzymes. Although the role of PARPs and poly(ADP-ribosyl)ation (PARylation) in cellular pathways, such as DNA repair and transcription, is well studied, the role of MARylation and MARTs (i.e., the PARP ‘monoenzymes’) are not well understood. Moreover, compared to PARPs, the development of MART-targeted therapeutics is in its infancy. Recent studies are beginning to shed light on the structural features, catalytic targets, and biological functions of MARTs. The development of new technologies to study MARTs have uncovered essential roles for these enzymes in the regulation of cellular processes, such as RNA metabolism, cellular transport, focal adhesion, and stress responses. These insights have increased our understanding of the biological functions of MARTs in cancers, neuronal development, and immune responses. Furthermore, several novel inhibitors of MARTs have been developed and are nearing clinical utility. In this review, we summarize the biological functions and molecular mechanisms of MARTs and MARylation, as well as recent advances in technology that have enabled detection and inhibition of their activity. We emphasize PARP-7, which is at the forefront of the MART subfamily with respect to understanding its biological roles and the development of therapeutically useful inhibitors. Collectively, the available studies reveal a growing understanding of the biochemistry, chemical biology, physiology, and pathology of MARTs.

scholarly journals Oligomeric and Fibrillar Species of Aβ42 Diversely Affect Human Neural Stem Cells

2021 ◽  
Vol 22 (17) ◽  
pp. 9537
Author(s):  
Adela Bernabeu-Zornoza ◽  
Raquel Coronel ◽  
Charlotte Palmer ◽  
Victoria López-Alonso ◽  
Isabel Liste
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Cell Fate ◽  
Molecular Mechanisms ◽  
Cellular Proliferation ◽  
Amyloid Β ◽  
Human Neural Stem Cells ◽  
High Concentrations ◽  
Aβ42 Peptide

Amyloid-β 42 peptide (Aβ1-42 (Aβ42)) is well-known for its involvement in the development of Alzheimer’s disease (AD). Aβ42 accumulates and aggregates in fibers that precipitate in the form of plaques in the brain causing toxicity; however, like other forms of Aβ peptide, the role of these peptides remains unclear. Here we analyze and compare the effects of oligomeric and fibrillary Aβ42 peptide on the biology (cell death, proliferative rate, and cell fate specification) of differentiating human neural stem cells (hNS1 cell line). By using the hNS1 cells we found that, at high concentrations, oligomeric and fibrillary Aβ42 peptides provoke apoptotic cellular death and damage of DNA in these cells, but Aβ42 fibrils have the strongest effect. The data also show that both oligomeric and fibrillar Aβ42 peptides decrease cellular proliferation but Aβ42 oligomers have the greatest effect. Finally, both, oligomers and fibrils favor gliogenesis and neurogenesis in hNS1 cells, although, in this case, the effect is more prominent in oligomers. All together the findings of this study may contribute to a better understanding of the molecular mechanisms involved in the pathology of AD and to the development of human neural stem cell-based therapies for AD treatment.

scholarly journals NADPH Oxidases: Redox Regulators of Stem Cell Fate and Function

Antioxidants ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 973
Author(s):  
Tullia Maraldi ◽  
Cristina Angeloni ◽  
Cecilia Prata ◽  
Silvana Hrelia
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Fate ◽  
Cell Biology ◽  
Immune Modulation ◽  
Ex Vivo ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Human Stem Cells ◽  
Stem Cell Fate

One of the major sources of reactive oxygen species (ROS) generated within stem cells is the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase family of enzymes (NOXs), which are critical determinants of the redox state beside antioxidant defense mechanisms. This balance is involved in another one that regulates stem cell fate: indeed, self-renewal, proliferation, and differentiation are decisive steps for stem cells during embryo development, adult tissue renovation, and cell therapy application. Ex vivo culture-expanded stem cells are being investigated for tissue repair and immune modulation, but events such as aging, senescence, and oxidative stress reduce their ex vivo proliferation, which is crucial for their clinical applications. Here, we review the role of NOX-derived ROS in stem cell biology and functions, focusing on positive and negative effects triggered by the activity of different NOX isoforms. We report recent findings on downstream molecular targets of NOX-ROS signaling that can modulate stem cell homeostasis and lineage commitment and discuss the implications in ex vivo expansion and in vivo engraftment, function, and longevity. This review highlights the role of NOX as a pivotal regulator of several stem cell populations, and we conclude that these aspects have important implications in the clinical utility of stem cells, but further studies on the effects of pharmacological modulation of NOX in human stem cells are imperative.

Classic and Novel Signaling Pathways Involved in Cancer: Targeting the NF-κB and Syk Signaling Pathways

2019 ◽  
Vol 14 (3) ◽  
pp. 219-225 ◽  
Author(s):  
Cong Tang ◽  
Guodong Zhu
Keyword(s):  
Cancer Therapy ◽  
Tyrosine Kinase ◽  
Signaling Pathways ◽  
Molecular Mechanisms ◽  
Therapeutic Potential ◽  
Cell Receptor ◽  
Transmembrane Receptors ◽  
Biological Responses ◽  
Different Types

The nuclear factor kappa B (NF-κB) consists of a family of transcription factors involved in the regulation of a wide variety of biological responses. Growing evidence support that NF-κB plays a major role in oncogenesis as well as its well-known function in the regulation of immune responses and inflammation. Therefore, we made a review of the diverse molecular mechanisms by which the NF-κB pathway is constitutively activated in different types of human cancers and the potential role of various oncogenic genes regulated by this transcription factor in cancer development and progression. We also discussed various pharmacological approaches employed to target the deregulated NF-κB signaling pathway and their possible therapeutic potential in cancer therapy. Moreover, Syk (Spleen tyrosine kinase), non-receptor tyrosine kinase which mediates signal transduction downstream of a variety of transmembrane receptors including classical immune-receptors like the B-cell receptor (BCR), which can also activate the inflammasome and NF-κB-mediated transcription of chemokines and cytokines in the presence of pathogens would be discussed as well. The highlight of this review article is to summarize the classic and novel signaling pathways involved in NF-κB and Syk signaling and then raise some possibilities for cancer therapy.

scholarly journals mRNA-Driven Generation of Transgene-Free Neural Stem Cells from Human Urine-Derived Cells

Cells ◽  
2019 ◽  
Vol 8 (9) ◽  
pp. 1043 ◽  
Author(s):  
Phil Jun Kang ◽  
Daryeon Son ◽  
Tae Hee Ko ◽  
Wonjun Hong ◽  
Wonjin Yun ◽  
...  
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Human Urine ◽  
Neurological Disorders ◽  
Therapeutic Potential ◽  
Embryonic Stem ◽  
Global Gene Expression ◽  
Patient Specific ◽  
Human Neural Stem Cells

Human neural stem cells (NSCs) hold enormous promise for neurological disorders, typically requiring their expandable and differentiable properties for regeneration of damaged neural tissues. Despite the therapeutic potential of induced NSCs (iNSCs), a major challenge for clinical feasibility is the presence of integrated transgenes in the host genome, contributing to the risk for undesired genotoxicity and tumorigenesis. Here, we describe the advanced transgene-free generation of iNSCs from human urine-derived cells (HUCs) by combining a cocktail of defined small molecules with self-replicable mRNA delivery. The established iNSCs were completely transgene-free in their cytosol and genome and further resembled human embryonic stem cell-derived NSCs in the morphology, biological characteristics, global gene expression, and potential to differentiate into functional neurons, astrocytes, and oligodendrocytes. Moreover, iNSC colonies were observed within eight days under optimized conditions, and no teratomas formed in vivo, implying the absence of pluripotent cells. This study proposes an approach to generate transplantable iNSCs that can be broadly applied for neurological disorders in a safe, efficient, and patient-specific manner.

scholarly journals Local anesthetics impair the growth and self-renewal of glioblastoma stem cells by inhibiting ZDHHC15-mediated GP130 palmitoylation

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Xiaoqing Fan ◽  
Haoran Yang ◽  
Chenggang Zhao ◽  
Lizhu Hu ◽  
Delong Wang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Western Blot ◽  
Local Anesthetics ◽  
Molecular Mechanisms ◽  
Biological Activities ◽  
Xenograft Model ◽  
Cell Counting ◽  
Migration And Invasion ◽  
Self Renewal

Abstract Background A large number of preclinical studies have shown that local anesthetics have a direct inhibitory effect on tumor biological activities, including cell survival, proliferation, migration, and invasion. There are few studies on the role of local anesthetics in cancer stem cells. This study aimed to determine the possible role of local anesthetics in glioblastoma stem cell (GSC) self-renewal and the underlying molecular mechanisms. Methods The effects of local anesthetics in GSCs were investigated through in vitro and in vivo assays (i.e., Cell Counting Kit 8, spheroidal formation assay, double immunofluorescence, western blot, and xenograft model). The acyl-biotin exchange method (ABE) assay was identified proteins that are S-acylated by zinc finger Asp-His-His-Cys-type palmitoyltransferase 15 (ZDHHC15). Western blot, co-immunoprecipitation, and liquid chromatograph mass spectrometer-mass spectrometry assays were used to explore the mechanisms of ZDHHC15 in effects of local anesthetics in GSCs. Results In this study, we identified a novel mechanism through which local anesthetics can damage the malignant phenotype of glioma. We found that local anesthetics prilocaine, lidocaine, procaine, and ropivacaine can impair the survival and self-renewal of GSCs, especially the classic glioblastoma subtype. These findings suggest that local anesthetics may weaken ZDHHC15 transcripts and decrease GP130 palmitoylation levels and membrane localization, thus inhibiting the activation of IL-6/STAT3 signaling. Conclusions In conclusion, our work emphasizes that ZDHHC15 is a candidate therapeutic target, and local anesthetics are potential therapeutic options for glioblastoma.

scholarly journals The Potential Association between the Risk of Post-Surgical Adhesion and the Activated Local Angiotensin II Type 1 Receptors: Need for Novel Treatment Strategies

2021 ◽  
pp. 1-8
Author(s):  
Mahmood Tavakkoli ◽  
Saeed Aali ◽  
Borzoo Khaledifar ◽  
Gordon A. Ferns ◽  
Majid Khazaei ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Therapeutic Potential ◽  
Angiotensin Receptor Blockers ◽  
Surgical Techniques ◽  
Treatment Strategies ◽  
Transforming Growth Factor Β

<b><i>Background:</i></b> Post-surgical adhesion bands (PSABs) are a common complication after abdominal or pelvic surgeries for different reasons like cancer treatment. Despite improvements in surgical techniques and the administration of drugs or the use of physical barriers, there has only been limited improvement in the frequency of postoperative adhesions. Complications of PSAB are pain, infertility, intestinal obstruction, and increased mortality. The most important molecular mechanisms for the development of PSAB are inflammatory response, oxidative stress, and overexpression of pro-fibrotic molecules such as transforming growth factor β. However, questions remain about the pathogenesis of this problem, for example, the causes for individual differences or why certain tissue sites are more prone to post-surgical adhesions. <b><i>Summary:</i></b> Addressing the pathological causes of PSAB, the potential role of local angiotensin II/angiotensin II type 1 receptors (AngII/AT1R), may help to prevent this problem. <b><i>Key Message:</i></b> The objective of this article was to explore the role of the AngII/AT1R axis potential to induce PSAB and the therapeutic potential of angiotensin receptor blockers in the prevention and treatment of PSAB.

Do Chimeras Have Minds?

2017 ◽  
Vol 26 (4) ◽  
pp. 577-591 ◽  
Author(s):  
BENJAMIN CAPPS
Keyword(s):  
Stem Cells ◽  
Human Brain ◽  
Nonhuman Primate ◽  
Moral Status ◽  
Neuronal Development ◽  
Nonhuman Animal ◽  
Brain Diseases ◽  
Human Being ◽  
Human Stem Cells ◽  
Human Neuron

Abstract:Suppose that a colleague proposed a fantastic experiment: to introduce human stem cells into a neonatal mouse so that its entire brain developed into “human-like” neuronal structures. The colleague claimed it would still be a mouse, and that its chimeric brain would be nothing like a “human” one. It would not, as a result, have a moral status beyond its nonhuman animal origins. Thus, the “human neuron mouse” would allow scientists to tinker with human-like neurology in ways that would be precluded if it were a human being, and that would promise to lead to substantial understanding of the destructive and incurable brain diseases that befall humanity. The colleague does admit, however, that for reasons of comparative fidelity, experiments in human patients would be scientifically preferable, although in this case, neither ethically justified nor legally permitted. For that reason, it might be desirable to create a human brain in a nonhuman primate, where it would be more likely that significant human-like neuronal development would occur, but still could not become a person. This article explores the significance of a “human neuron chimpanzee,” and suggests that contradictions in the design of the experiment make it unethical to proceed in either murine or primate models.

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