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Neural Stem Cells: Focusing on Disease Modeling and Translational Application

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (15 October 2023) | Viewed by 12072

Special Issue Editors

Cellular Reprogramming Unit, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy
Interests: iPSC; neurodevelopmental diseases; neurodegenerative diseases; drug screening; epigenetics
Special Issues, Collections and Topics in MDPI journals
Department of Biotechnology and Biosciences, University of Milano-Bicocca, Piazza della Scienza 2, 20126 Milan, Italy
Interests: neurodegenerative diseases; amyotrophic lateral sclerosis; pre-clinical studies; animal models
Special Issues, Collections and Topics in MDPI journals
Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy
Interests: stem cells; clinical trial; advanced therapies; cancer stem cells
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues, 

The aim of this issue is to bring together international experts to provide both comprehensive overviews for and original contributions to this dynamic research field. During the last century, the progress in neural stem cell biology has revolutionized the way we study and treat diseases, transforming both the fields of science and medicine.

The present issue focuses on the use of neural stem cells (derived from different sources, including iPSC) in basic and translational research, starting from the cellular models necessary to define the mechanisms underlying neurodegenerative/neurodevelopmental diseases, and progressing to preclinical studies and drug screening approaches.

This Special Issue includes the following contributions:

  1. The strategies adopted to direct the differentiation of neural stem cells and define disease models;
  2. The variety of pathological mechanisms that could be addressed by these approaches;
  3. The methodologies used to screen candidate compounds, validate their efficacy, and accelerate drug development;
  4. The preclinical studies allowing for the translation of the scientific knowledge obtained through neural stem cells into potential therapeutic treatments.

The present issue is also open to the individuals working in the area of multidisciplinary studies, who create materials or use technologies to convey the cells to the injection site, improving both their engraftment and differentiation.

Dr. Jessica Rosati
Dr. Daniela Ferrari
Prof. Dr. Angelo Luigi Vescovi
Guest Editors

Manuscript Submission Information

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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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

  • neural stem cells
  • disease models
  • neurodegenerative/neurodevelopmental disease
  • pathological mechanism dissection
  • biomaterials
  • drug screening

Published Papers (7 papers)

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Research

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25 pages, 4624 KiB  
Article
Transcriptional Dysregulation and Impaired Neuronal Activity in FMR1 Knock-Out and Fragile X Patients’ iPSC-Derived Models
by Gilles Maussion, Cecilia Rocha, Narges Abdian, Dimitri Yang, Julien Turk, Dulce Carrillo Valenzuela, Luisa Pimentel, Zhipeng You, Barbara Morquette, Michael Nicouleau, Eric Deneault, Samuel Higgins, Carol X.-Q. Chen, Wolfgang E. Reintsch, Stanley Ho, Vincent Soubannier, Sarah Lépine, Zora Modrusan, Jessica Lund, William Stephenson, Rajib Schubert and Thomas M. Durcanadd Show full author list remove Hide full author list
Int. J. Mol. Sci. 2023, 24(19), 14926; https://doi.org/10.3390/ijms241914926 - 05 Oct 2023
Cited by 1 | Viewed by 1509
Abstract
Fragile X syndrome (FXS) is caused by a repression of the FMR1 gene that codes the Fragile X mental retardation protein (FMRP), an RNA binding protein involved in processes that are crucial for proper brain development. To better understand the consequences of the [...] Read more.
Fragile X syndrome (FXS) is caused by a repression of the FMR1 gene that codes the Fragile X mental retardation protein (FMRP), an RNA binding protein involved in processes that are crucial for proper brain development. To better understand the consequences of the absence of FMRP, we analyzed gene expression profiles and activities of cortical neural progenitor cells (NPCs) and neurons obtained from FXS patients’ induced pluripotent stem cells (IPSCs) and IPSC-derived cells from FMR1 knock-out engineered using CRISPR-CAS9 technology. Multielectrode array recordings revealed in FMR1 KO and FXS patient cells, decreased mean firing rates; activities blocked by tetrodotoxin application. Increased expression of presynaptic mRNA and transcription factors involved in the forebrain specification and decreased levels of mRNA coding AMPA and NMDA subunits were observed using RNA sequencing on FMR1 KO neurons and validated using quantitative PCR in both models. Intriguingly, 40% of the differentially expressed genes were commonly deregulated between NPCs and differentiating neurons with significant enrichments in FMRP targets and autism-related genes found amongst downregulated genes. Our findings suggest that the absence of FMRP affects transcriptional profiles since the NPC stage, and leads to impaired activity and neuronal differentiation over time, which illustrates the critical role of FMRP protein in neuronal development. Full article
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18 pages, 4303 KiB  
Article
Amyloid Precursor Protein (APP) Regulates Gliogenesis and Neurogenesis of Human Neural Stem Cells by Several Signaling Pathways
by Raquel Coronel, Adela Bernabeu-Zornoza, Charlotte Palmer, Rosa González-Sastre, Andreea Rosca, Patricia Mateos-Martínez, Victoria López-Alonso and Isabel Liste
Int. J. Mol. Sci. 2023, 24(16), 12964; https://doi.org/10.3390/ijms241612964 - 19 Aug 2023
Cited by 2 | Viewed by 1208
Abstract
Numerous studies have focused on the pathophysiological role of amyloid precursor protein (APP) because the proteolytic processing of APP to β-amyloid (Aβ) peptide is a central event in Alzheimer’s disease (AD). However, many authors consider that alterations in the physiological functions of APP [...] Read more.
Numerous studies have focused on the pathophysiological role of amyloid precursor protein (APP) because the proteolytic processing of APP to β-amyloid (Aβ) peptide is a central event in Alzheimer’s disease (AD). However, many authors consider that alterations in the physiological functions of APP are likely to play a key role in AD. Previous studies in our laboratory revealed that APP plays an important role in the differentiation of human neural stem cells (hNSCs), favoring glial differentiation (gliogenesis) and preventing their differentiation toward a neuronal phenotype (neurogenesis). In the present study, we have evaluated the effects of APP overexpression in hNSCs at a global gene level by a transcriptomic analysis using the massive RNA sequencing (RNA-seq) technology. Specifically, we have focused on differentially expressed genes that are related to neuronal and glial differentiation processes, as well as on groups of differentially expressed genes associated with different signaling pathways, in order to find a possible interaction between them and APP. Our data indicate a differential expression in genes related to Notch, Wnt, PI3K-AKT, and JAK-STAT signaling, among others. Knowledge of APP biological functions, as well as the possible signaling pathways that could be related to this protein, are essential to advance our understanding of AD. Full article
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15 pages, 4922 KiB  
Article
Effectiveness of Combinational Treatments for Alzheimer’s Disease with Human Neural Stem Cells and Microglial Cells Over-Expressing Functional Genes
by Young-Hwan Ban, Dongsun Park, Ehn-Kyoung Choi, Tae Myoung Kim, Seong Soo Joo and Yun-Bae Kim
Int. J. Mol. Sci. 2023, 24(11), 9561; https://doi.org/10.3390/ijms24119561 - 31 May 2023
Cited by 1 | Viewed by 1260
Abstract
Alzheimer’s disease (AD) is one of the most common neurodegenerative diseases. In AD patients, amyloid-β (Aβ) peptide-mediated degeneration of the cholinergic system utilizing acetylcholine (ACh) for memory acquisition is observed. Since AD therapy using acetylcholinesterase (AChE) inhibitors are only palliative for memory deficits [...] Read more.
Alzheimer’s disease (AD) is one of the most common neurodegenerative diseases. In AD patients, amyloid-β (Aβ) peptide-mediated degeneration of the cholinergic system utilizing acetylcholine (ACh) for memory acquisition is observed. Since AD therapy using acetylcholinesterase (AChE) inhibitors are only palliative for memory deficits without reversing disease progress, there is a need for effective therapies, and cell-based therapeutic approaches should fulfil this requirement. We established F3.ChAT human neural stem cells (NSCs) encoding the choline acetyltransferase (ChAT) gene, an ACh-synthesizing enzyme, HMO6.NEP human microglial cells encoding the neprilysin (NEP) gene, an Aβ-degrading enzyme, and HMO6.SRA cells encoding the scavenger receptor A (SRA) gene, an Aβ-uptaking receptor. For the efficacy evaluation of the cells, first, we established an appropriate animal model based on Aβ accumulation and cognitive dysfunction. Among various AD models, intracerebroventricular (ICV) injection of ethylcholine mustard azirinium ion (AF64A) induced the most severe Aβ accumulation and memory dysfunction. Established NSCs and HMO6 cells were transplanted ICV to mice showing memory loss induced by AF64A challenge, and brain Aβ accumulation, ACh concentration and cognitive function were analyzed. All the transplanted F3.ChAT, HMO6.NEP and HMO6.SRA cells were found to survive up to 4 weeks in the mouse brain and expressed their functional genes. Combinational treatment with the NSCs (F3.ChAT) and microglial cells encoding each functional gene (HMO6.NEP or HMO6.SRA) synergistically restored the learning and memory function of AF64A-challenged mice by eliminating Aβ deposits and recovering ACh level. The cells also attenuated inflammatory astrocytic (glial fibrillary acidic protein) response by reducing Aβ accumulation. Taken together, it is expected that NSCs and microglial cells over-expressing ChAT, NEP or SRA genes could be strategies for replacement cell therapy of AD. Full article
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13 pages, 2304 KiB  
Communication
Human Neural Stem Cell-Based Drug Product: Clinical and Nonclinical Characterization
by Daniela Celeste Profico, Maurizio Gelati, Daniela Ferrari, Giada Sgaravizzi, Claudia Ricciolini, Massimo Projetti Pensi, Gianmarco Muzi, Laura Cajola, Massimiliano Copetti, Emilio Ciusani, Raffaele Pugliese, Fabrizio Gelain and Angelo Luigi Vescovi
Int. J. Mol. Sci. 2022, 23(21), 13425; https://doi.org/10.3390/ijms232113425 - 03 Nov 2022
Cited by 4 | Viewed by 1463
Abstract
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 [...] Read more.
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. Full article
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9 pages, 711 KiB  
Communication
Multi-Omic Investigations of a 17–19 Translocation Links MINK1 Disruption to Autism, Epilepsy and Osteoporosis
by Jesper Eisfeldt, Jakob Schuy, Eva-Lena Stattin, Malin Kvarnung, Anna Falk, Lars Feuk and Anna Lindstrand
Int. J. Mol. Sci. 2022, 23(16), 9392; https://doi.org/10.3390/ijms23169392 - 20 Aug 2022
Cited by 2 | Viewed by 1792
Abstract
Balanced structural variants, such as reciprocal translocations, are sometimes hard to detect with sequencing, especially when the breakpoints are located in repetitive or insufficiently mapped regions of the genome. In such cases, long-range information is required to resolve the rearrangement, identify disrupted genes [...] Read more.
Balanced structural variants, such as reciprocal translocations, are sometimes hard to detect with sequencing, especially when the breakpoints are located in repetitive or insufficiently mapped regions of the genome. In such cases, long-range information is required to resolve the rearrangement, identify disrupted genes and, in symptomatic carriers, pinpoint the disease-causing mechanisms. Here, we report an individual with autism, epilepsy and osteoporosis and a de novo balanced reciprocal translocation: t(17;19) (p13;p11). The genomic DNA was analyzed by short-, linked- and long-read genome sequencing, as well as optical mapping. Transcriptional consequences were assessed by transcriptome sequencing of patient-specific neuroepithelial stem cells derived from induced pluripotent stem cells (iPSC). The translocation breakpoints were only detected by long-read sequencing, the first on 17p13, located between exon 1 and exon 2 of MINK1 (Misshapen-like kinase 1), and the second in the chromosome 19 centromere. Functional validation in induced neural cells showed that MINK1 expression was reduced by >50% in the patient’s cells compared to healthy control cells. Furthermore, pathway analysis revealed an enrichment of changed neural pathways in the patient’s cells. Altogether, our multi-omics experiments highlight MINK1 as a candidate monogenic disease gene and show the advantages of long-read genome sequencing in capturing centromeric translocations. Full article
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29 pages, 12847 KiB  
Article
Bridging between Mouse and Human Enhancer-Promoter Long-Range Interactions in Neural Stem Cells, to Understand Enhancer Function in Neurodevelopmental Disease
by Romina D’Aurizio, Orazio Catona, Mattia Pitasi, Yang Eric Li, Bing Ren and Silvia Kirsten Nicolis
Int. J. Mol. Sci. 2022, 23(14), 7964; https://doi.org/10.3390/ijms23147964 - 19 Jul 2022
Cited by 4 | Viewed by 2777
Abstract
Non-coding variation in complex human disease has been well established by genome-wide association studies, and is thought to involve regulatory elements, such as enhancers, whose variation affects the expression of the gene responsible for the disease. The regulatory elements often lie far from [...] Read more.
Non-coding variation in complex human disease has been well established by genome-wide association studies, and is thought to involve regulatory elements, such as enhancers, whose variation affects the expression of the gene responsible for the disease. The regulatory elements often lie far from the gene they regulate, or within introns of genes differing from the regulated gene, making it difficult to identify the gene whose function is affected by a given enhancer variation. Enhancers are connected to their target gene promoters via long-range physical interactions (loops). In our study, we re-mapped, onto the human genome, more than 10,000 enhancers connected to promoters via long-range interactions, that we had previously identified in mouse brain-derived neural stem cells by RNApolII-ChIA-PET analysis, coupled to ChIP-seq mapping of DNA/chromatin regions carrying epigenetic enhancer marks. These interactions are thought to be functionally relevant. We discovered, in the human genome, thousands of DNA regions syntenic with the interacting mouse DNA regions (enhancers and connected promoters). We further annotated these human regions regarding their overlap with sequence variants (single nucleotide polymorphisms, SNPs; copy number variants, CNVs), that were previously associated with neurodevelopmental disease in humans. We document various cases in which the genetic variant, associated in humans to neurodevelopmental disease, affects an enhancer involved in long-range interactions: SNPs, previously identified by genome-wide association studies to be associated with schizophrenia, bipolar disorder, and intelligence, are located within our human syntenic enhancers, and alter transcription factor recognition sites. Similarly, CNVs associated to autism spectrum disease and other neurodevelopmental disorders overlap with our human syntenic enhancers. Some of these enhancers are connected (in mice) to homologs of genes already associated to the human disease, strengthening the hypothesis that the gene is indeed involved in the disease. Other enhancers are connected to genes not previously associated with the disease, pointing to their possible pathogenetic involvement. Our observations provide a resource for further exploration of neural disease, in parallel with the now widespread genome-wide identification of DNA variants in patients with neural disease. Full article
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Review

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12 pages, 2075 KiB  
Review
Two Sides of The Same Coin: Normal and Tumoral Stem Cells, The Relevance of In Vitro Models and Therapeutic Approaches: The Experience with Zika Virus in Nervous System Development and Glioblastoma Treatment
by Rosaria Tinnirello, Cinzia Maria Chinnici, Vitale Miceli, Rosalia Busà, Matteo Bulati, Alessia Gallo, Giovanni Zito, Pier Giulio Conaldi and Gioacchin Iannolo
Int. J. Mol. Sci. 2023, 24(17), 13550; https://doi.org/10.3390/ijms241713550 - 31 Aug 2023
Cited by 3 | Viewed by 1006
Abstract
Neural stem cells (NSCs) were described for the first time more than two decades ago for their ability to differentiate into all neural cell lineages. The isolation of NSCs from adults and embryos was carried out by various laboratories and in different species, [...] Read more.
Neural stem cells (NSCs) were described for the first time more than two decades ago for their ability to differentiate into all neural cell lineages. The isolation of NSCs from adults and embryos was carried out by various laboratories and in different species, from mice to humans. Similarly, no more than two decades ago, cancer stem cells were described. Cancer stem cells, previously identified in hematological malignancies, have now been isolated from several solid tumors (breast, brain, and gastrointestinal compartment). Though the origin of these cells is still unknown, there is a wide consensus about their role in tumor onset, propagation and, in particular, resistance to treatments. Normal and neoplastic neural stem cells share common characteristics, and can thus be considered as two sides of the same coin. This is particularly true in the case of the Zika virus (ZIKV), which has been described as an inhibitor of neural development by specifically targeting NSCs. This understanding prompted us and other groups to evaluate ZIKV action in glioblastoma stem cells (GSCs). The results indicate an oncolytic activity of this virus vs. GSCs, opening potentially new possibilities in glioblastoma treatment. Full article
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