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Neural Stem Cells: Developmental Mechanisms and Disease Modelling
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Neural Stem Cells: Developmental Mechanisms and Disease Modelling

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

Deadline for manuscript submissions: closed (31 August 2022) | Viewed by 55249

Special Issue Editor

Prof. Dr. Leonora Buzanska

E-Mail Website
Guest Editor
Mossakowski Medical Research Centre Polish Academy of Sciences, Department of Stem Cell Bioengineering, Warsaw, Poland
Interests: stem cell bioengineering; cerebral organoids; modeling neural disorders; developmental neurotoxicity

Special Issue Information

Dear Colleagues,

In the present Special Issue of Cells: “Neural Stem Cells: Developmental Mechanisms and Disease Modelling,” authors are cordially invited to contribute articles presenting original data as well as reviews updating progress in the neural stem cells field, including molecular mechanisms of neurogenesis and modelling of neural disorders and modern technologies implemented to enable such progress.

The process of conventional reprogramming of somatic cells to induced pluripotent stem cells (iPSC) and their further differentiation to desired phenotype co-opts developmental programs and results in intermediate phenotypes (e.g., neural progenitors or immature neurons), while direct reprogramming (e.g., fibroblasts into moto-neurons) bypasses developmental events and results in mature phenotypes, preserving aging and regional diversity. On the other hand, the interest of scientists is also focused on “forward programming” of pluripotent stem cells toward specific neural subtypes, a novel strategy of reprogramming based on cell fate specification by basic-helix-loop-helix transcription factors. In addition, modern tools of bioinformatics employing gene-library screening artificial intelligence and machine learning solutions predict in silico developmental trajectories and pick up developmental risk factors. Identifying the key predictors of terminal maturation as early as the neural progenitor stage allows researchers to establish novel protocols to obtain a specific population of mature neurons.

The expanding field of brain organoids enables spatiotemporal recapitulation of early human CNS development in vitro, as well as modelling neurodevelopmental and neurodegenerative diseases. The recent advances in stem cell protocols, gene editing technology, and microenvironmental bioengineering, as well as the new methods for inducing and detecting molecular processes in both leaving and fixed cells (e.g., optogenetic solutions, single cell sequencing, single cell mass cytometry) has enabled breakthrough discoveries in neuroscience. This has already led to the development of clinical grade cell drug products which were successfully applied to novel, promising clinical trials. Last but not least is the strategy of in vivo direct cell conversion into the desired type of functional neurons (e.g., astrocytes into GABA-ergic neurons or moto-neurons) as a promising therapeutic tool in the treatment of stroke, drug-resistant epilepsy or neurodegenerative disorders.

The molecular mechanisms of different aspects of conventional and direct reprogramming strategies leading to specific neuronal subtypes as well as major achievements in brain organoid technology modelling neurodevelopment and disease are greatly welcome in this Special Issue.

We are looking forward to your contributions to this Special Issue.

Prof. Dr. Leonora Buzanska
Guest Editor

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Keywords

  • neural stem cells
  • molecular mechanisms of neurogenesis
  • direct reprogramming
  • forward programming
  • brain organoids
  • modeling of neurodevelopment and neurological diseases

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Published Papers (14 papers)

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Research

Jump to: Review

29 pages, 10632 KiB  
Article
Understanding Intra- and Inter-Species Variability in Neural Stem Cells’ Biology Is Key to Their Successful Cryopreservation, Culture, and Propagation
by Klaudia Radoszkiewicz, Katarzyna Jezierska-Woźniak, Tomasz Waśniewski and Anna Sarnowska
Cells 2023, 12(3), 488; https://doi.org/10.3390/cells12030488 - 2 Feb 2023
Cited by 2 | Viewed by 2032
Abstract
Although clinical trials on human neural stem cells (hNSCs) have already been implemented in the treatment of neurological diseases and they have demonstrated their therapeutic effects, many questions remain in the field of preclinical research regarding the biology of these cells, their therapeutic [...] Read more.
Although clinical trials on human neural stem cells (hNSCs) have already been implemented in the treatment of neurological diseases and they have demonstrated their therapeutic effects, many questions remain in the field of preclinical research regarding the biology of these cells, their therapeutic properties, and their neurorestorative potential. Unfortunately, scientific reports are inconsistent and much of the NSCs research has been conducted on rodents rather than human cells for ethical reasons or due to insufficient cell material. Therefore, a question arises as to whether or which conclusions drawn on the isolation, cell survival, proliferation, or cell fate observed in vitro in rodent NSCs can be introduced into clinical applications. This paper presents the effects of different spatial, nutritional, and dissociation conditions on NSCs’ functional properties, which are highly species-dependent. Our study confirmed that the discrepancies in the available literature on NSCs survival, proliferation, and fate did not only depend on intra-species factors and applied environmental conditions, but they were also affected by significant inter-species variability. Human and rodent NSCs share one feature, i.e., the necessity to be cultured immediately after isolation, which significantly maintains their survival. Additionally, in the absence of experiments on human cells, rat NSCs biology (neurosphere formation potential and neural differentiation stage) seems closer to that of humans rather than mice in response to environmental factors. Full article
(This article belongs to the Special Issue Neural Stem Cells: Developmental Mechanisms and Disease Modelling)
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25 pages, 4301 KiB  
Article
Genes Involved in DNA Repair and Mitophagy Protect Embryoid Bodies from the Toxic Effect of Methylmercury Chloride under Physioxia Conditions
by Justyna Augustyniak, Hanna Kozlowska and Leonora Buzanska
Cells 2023, 12(3), 390; https://doi.org/10.3390/cells12030390 - 21 Jan 2023
Viewed by 1811
Abstract
The formation of embryoid bodies (EBs) from human pluripotent stem cells resembles the early stages of human embryo development, mimicking the organization of three germ layers. In our study, EBs were tested for their vulnerability to chronic exposure to low doses of MeHgCl [...] Read more.
The formation of embryoid bodies (EBs) from human pluripotent stem cells resembles the early stages of human embryo development, mimicking the organization of three germ layers. In our study, EBs were tested for their vulnerability to chronic exposure to low doses of MeHgCl (1 nM) under atmospheric (21%O2) and physioxia (5%O2) conditions. Significant differences were observed in the relative expression of genes associated with DNA repair and mitophagy between the tested oxygen conditions in nontreated EBs. When compared to physioxia conditions, the significant differences recorded in EBs cultured at 21% O2 included: (1) lower expression of genes associated with DNA repair (ATM, OGG1, PARP1, POLG1) and mitophagy (PARK2); (2) higher level of mtDNA copy number; and (3) higher expression of the neuroectodermal gene (NES). Chronic exposure to a low dose of MeHgCl (1 nM) disrupted the development of EBs under both oxygen conditions. However, only EBs exposed to MeHgCl at 21% O2 revealed downregulation of mtDNA copy number, increased oxidative DNA damage and DNA fragmentation, as well as disturbances in SOX17 (endoderm) and TBXT (mesoderm) genes expression. Our data revealed that physioxia conditions protected EBs genome integrity and their further differentiation. Full article
(This article belongs to the Special Issue Neural Stem Cells: Developmental Mechanisms and Disease Modelling)
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14 pages, 4104 KiB  
Article
The Generation of Human iPSC Lines from Three Individuals with Dravet Syndrome and Characterization of Neural Differentiation Markers in iPSC-Derived Ventral Forebrain Organoid Model
by Valery Zayat, Zuzanna Kuczynska, Michal Liput, Erkan Metin, Sylwia Rzonca-Niewczas, Marta Smyk, Tomasz Mazurczak, Alicja Goszczanska-Ciuchta, Pawel Leszczynski, Dorota Hoffman-Zacharska and Leonora Buzanska
Cells 2023, 12(2), 339; https://doi.org/10.3390/cells12020339 - 16 Jan 2023
Cited by 4 | Viewed by 3195
Abstract
Dravet syndrome (DRVT) is a rare form of neurodevelopmental disorder with a high risk of sudden unexpected death in epilepsy (SUDEP), caused mainly (>80% cases) by mutations in the SCN1A gene, coding the Nav1.1 protein (alfa-subunit of voltage-sensitive sodium channel). Mutations in SCN1A [...] Read more.
Dravet syndrome (DRVT) is a rare form of neurodevelopmental disorder with a high risk of sudden unexpected death in epilepsy (SUDEP), caused mainly (>80% cases) by mutations in the SCN1A gene, coding the Nav1.1 protein (alfa-subunit of voltage-sensitive sodium channel). Mutations in SCN1A are linked to heterogenous epileptic phenotypes of various types, severity, and patient prognosis. Here we generated iPSC lines from fibroblasts obtained from three individuals affected with DRVT carrying distinct mutations in the SCN1A gene (nonsense mutation p.Ser1516*, missense mutation p.Arg1596His, and splicing mutation c.2589+2dupT). The iPSC lines, generated with the non-integrative approach, retained the distinct SCN1A gene mutation of the donor fibroblasts and were characterized by confirming the expression of the pluripotency markers, the three-germ layer differentiation potential, the absence of exogenous vector expression, and a normal karyotype. The generated iPSC lines were used to establish ventral forebrain organoids, the most affected type of neurons in the pathology of DRVT. The DRVT organoid model will provide an additional resource for deciphering the pathology behind Nav1.1 haploinsufficiency and drug screening to remediate the functional deficits associated with the disease. Full article
(This article belongs to the Special Issue Neural Stem Cells: Developmental Mechanisms and Disease Modelling)
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18 pages, 5116 KiB  
Article
CBP and p300 Jointly Maintain Neural Progenitor Viability but Play Unique Roles in the Differentiation of Neural Lineages
by Rocío González-Martínez, Angel Márquez-Galera, Beatriz Del Blanco, Jose P. López-Atalaya, Angel Barco and Eloísa Herrera
Cells 2022, 11(24), 4118; https://doi.org/10.3390/cells11244118 - 18 Dec 2022
Cited by 3 | Viewed by 2953
Abstract
The paralogous lysine acetyltransferases 3 (KAT3), CBP and P300, play critical roles during neurodevelopment, but their specific roles in neural precursors maintenance and differentiation remain obscure. In fact, it is still unclear whether these proteins are individually or jointly essential in processes such [...] Read more.
The paralogous lysine acetyltransferases 3 (KAT3), CBP and P300, play critical roles during neurodevelopment, but their specific roles in neural precursors maintenance and differentiation remain obscure. In fact, it is still unclear whether these proteins are individually or jointly essential in processes such as proliferation of neural precursors, differentiation to specific neural cell types, or both. Here, we use subventricular zone-derived neurospheres as a potential ex vivo developmental model to analyze the proliferation and differentiation of neural stem cells (NSCs) lacking CBP, p300, or both proteins. The results showed that CBP and p300 are not individually essential for maintenance and proliferation of NSCs, although their combined ablation seriously compromised cell division. In turn, the absence of either of the two proteins compromised the differentiation of NSC into the neuronal and astrocytic lineages. Single-nucleus RNA sequencing analysis of neural cell cultures derived from CBP or p300 mutant neurospheres revealed divergent trajectories of neural differentiation upon CBP or p300 ablation, confirming unique functions and nonredundant roles in neural development. These findings contribute to a better understanding of the shared and individual roles of KAT3 proteins in neural differentiation and the etiology of neurodevelopmental disorders caused by their deficiency. Full article
(This article belongs to the Special Issue Neural Stem Cells: Developmental Mechanisms and Disease Modelling)
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14 pages, 5900 KiB  
Article
Enteric Neural Network Assembly Was Promoted by Basic Fibroblast Growth Factor and Vitamin A but Inhibited by Epidermal Growth Factor
by Jeng-Chang Chen, Wendy Yang, Li-Yun Tseng and Hsueh-Ling Chang
Cells 2022, 11(18), 2841; https://doi.org/10.3390/cells11182841 - 12 Sep 2022
Cited by 3 | Viewed by 1973
Abstract
Extending well beyond the original use of propagating neural precursors from the central nervous system and dorsal root ganglia, neurosphere medium (NSM) and self-renewal medium (SRM) are two distinct formulas with widespread popularity in enteric neural stem cell (ENSC) applications. However, it remains [...] Read more.
Extending well beyond the original use of propagating neural precursors from the central nervous system and dorsal root ganglia, neurosphere medium (NSM) and self-renewal medium (SRM) are two distinct formulas with widespread popularity in enteric neural stem cell (ENSC) applications. However, it remains unknown what growth factors or nutrients are crucial to ENSC development, let alone whether the discrepancy in their components may affect the outcomes of ENSC culture. Dispersed enterocytes from murine fetal gut were nurtured in NSM, SRM or their modifications by selective component elimination or addition to assess their effects on ENSC development. NSM generated neuriteless neurospheres, whereas SRM, even deprived of chicken embryo extract, might wire ganglia together to assemble neural networks. The distinct outcomes came from epidermal growth factor, which inhibited enteric neuronal wiring in NSM. In contrast, basic fibroblast growth factor promoted enteric neurogenesis, gangliogenesis, and neuronal wiring. Moreover, vitamin A derivatives might facilitate neuronal maturation evidenced by p75 downregulation during ENSC differentiation toward enteric neurons to promote gangliogenesis and network assembly. Our results might help to better manipulate ENSC propagation and differentiation in vitro, and open a new avenue for the study of enteric neuronal neuritogenesis and synaptogenesis. Full article
(This article belongs to the Special Issue Neural Stem Cells: Developmental Mechanisms and Disease Modelling)
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27 pages, 9912 KiB  
Article
Neurogenic and Neuroprotective Potential of Stem/Stromal Cells Derived from Adipose Tissue
by Anna Figiel-Dabrowska, Klaudia Radoszkiewicz, Paulina Rybkowska, Natalia Ewa Krzesniak, Dorota Sulejczak and Anna Sarnowska
Cells 2021, 10(6), 1475; https://doi.org/10.3390/cells10061475 - 11 Jun 2021
Cited by 18 | Viewed by 3790
Abstract
Currently, the number of stem-cell based experimental therapies in neurological injuries and neurodegenerative disorders has been massively increasing. Despite the fact that we still have not obtained strong evidence of mesenchymal stem/stromal cells’ neurogenic effectiveness in vivo, research may need to focus on [...] Read more.
Currently, the number of stem-cell based experimental therapies in neurological injuries and neurodegenerative disorders has been massively increasing. Despite the fact that we still have not obtained strong evidence of mesenchymal stem/stromal cells’ neurogenic effectiveness in vivo, research may need to focus on more appropriate sources that result in more therapeutically promising cell populations. In this study, we used dedifferentiated fat cells (DFAT) that are proven to demonstrate more pluripotent abilities in comparison with standard adipose stromal cells (ASCs). We used the ceiling culture method to establish DFAT cells and to optimize culture conditions with the use of a physioxic environment (5% O2). We also performed neural differentiation tests and assessed the neurogenic and neuroprotective capability of both DFAT cells and ASCs. Our results show that DFAT cells may have a better ability to differentiate into oligodendrocytes, astrocytes, and neuron-like cells, both in culture supplemented with N21 and in co-culture with oxygen–glucose-deprived (OGD) hippocampal organotypic slice culture (OHC) in comparison with ASCs. Results also show that DFAT cells have a different secretory profile than ASCs after contact with injured tissue. In conclusion, DFAT cells constitute a distinct subpopulation and may be an alternative source in cell therapy for the treatment of nervous system disorders. Full article
(This article belongs to the Special Issue Neural Stem Cells: Developmental Mechanisms and Disease Modelling)
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14 pages, 2033 KiB  
Article
Modeling CNS Involvement in Pompe Disease Using Neural Stem Cells Generated from Patient-Derived Induced Pluripotent Stem Cells
by Yu-Shan Cheng, Shu Yang, Junjie Hong, Rong Li, Jeanette Beers, Jizhong Zou, Wenwei Huang and Wei Zheng
Cells 2021, 10(1), 8; https://doi.org/10.3390/cells10010008 - 22 Dec 2020
Cited by 10 | Viewed by 3233
Abstract
Pompe disease is a lysosomal storage disorder caused by autosomal recessive mutations in the acid alpha-glucosidase (GAA) gene. Acid alpha-glucosidase deficiency leads to abnormal glycogen accumulation in patient cells. Given the increasing evidence of central nervous system (CNS) involvement in classic infantile Pompe [...] Read more.
Pompe disease is a lysosomal storage disorder caused by autosomal recessive mutations in the acid alpha-glucosidase (GAA) gene. Acid alpha-glucosidase deficiency leads to abnormal glycogen accumulation in patient cells. Given the increasing evidence of central nervous system (CNS) involvement in classic infantile Pompe disease, we used neural stem cells, differentiated from patient induced pluripotent stem cells, to model the neuronal phenotype of Pompe disease. These Pompe neural stem cells exhibited disease-related phenotypes including glycogen accumulation, increased lysosomal staining, and secondary lipid buildup. These morphological phenotypes in patient neural stem cells provided a tool for drug efficacy evaluation. Two potential therapeutic agents, hydroxypropyl-β-cyclodextrin and δ-tocopherol, were tested along with recombinant human acid alpha-glucosidase (rhGAA) in this cell-based Pompe model. Treatment with rhGAA reduced LysoTracker staining in Pompe neural stem cells, indicating reduced lysosome size. Additionally, treatment of diseased neural stem cells with the combination of hydroxypropyl-β-cyclodextrin and δ-tocopherol significantly reduced the disease phenotypes. These results demonstrated patient-derived Pompe neural stem cells could be used as a model to study disease pathogenesis, to evaluate drug efficacy, and to screen compounds for drug discovery in the context of correcting CNS defects. Full article
(This article belongs to the Special Issue Neural Stem Cells: Developmental Mechanisms and Disease Modelling)
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Review

Jump to: Research

17 pages, 1125 KiB  
Review
Advanced 3D Models of Human Brain Tissue Using Neural Cell Lines: State-of-the-Art and Future Prospects
by Rachele Fabbri, Ludovica Cacopardo, Arti Ahluwalia and Chiara Magliaro
Cells 2023, 12(8), 1181; https://doi.org/10.3390/cells12081181 - 18 Apr 2023
Cited by 8 | Viewed by 3615
Abstract
Human-relevant three-dimensional (3D) models of cerebral tissue can be invaluable tools to boost our understanding of the cellular mechanisms underlying brain pathophysiology. Nowadays, the accessibility, isolation and harvesting of human neural cells represents a bottleneck for obtaining reproducible and accurate models and gaining [...] Read more.
Human-relevant three-dimensional (3D) models of cerebral tissue can be invaluable tools to boost our understanding of the cellular mechanisms underlying brain pathophysiology. Nowadays, the accessibility, isolation and harvesting of human neural cells represents a bottleneck for obtaining reproducible and accurate models and gaining insights in the fields of oncology, neurodegenerative diseases and toxicology. In this scenario, given their low cost, ease of culture and reproducibility, neural cell lines constitute a key tool for developing usable and reliable models of the human brain. Here, we review the most recent advances in 3D constructs laden with neural cell lines, highlighting their advantages and limitations and their possible future applications. Full article
(This article belongs to the Special Issue Neural Stem Cells: Developmental Mechanisms and Disease Modelling)
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35 pages, 2880 KiB  
Review
Direct Cell Reprogramming and Phenotypic Conversion: An Analysis of Experimental Attempts to Transform Astrocytes into Neurons in Adult Animals
by Rachel Dennison, Esteban Usuga, Harriet Chen, Jacob Z. Paul, Christian A. Arbelaez and Yang D. Teng
Cells 2023, 12(4), 618; https://doi.org/10.3390/cells12040618 - 14 Feb 2023
Cited by 3 | Viewed by 4454
Abstract
Central nervous system (CNS) repair after injury or disease remains an unresolved problem in neurobiology research and an unmet medical need. Directly reprogramming or converting astrocytes to neurons (AtN) in adult animals has been investigated as a potential strategy to facilitate brain and [...] Read more.
Central nervous system (CNS) repair after injury or disease remains an unresolved problem in neurobiology research and an unmet medical need. Directly reprogramming or converting astrocytes to neurons (AtN) in adult animals has been investigated as a potential strategy to facilitate brain and spinal cord recovery and advance fundamental biology. Conceptually, AtN strategies rely on forced expression or repression of lineage-specific transcription factors to make endogenous astrocytes become “induced neurons” (iNs), presumably without re-entering any pluripotent or multipotent states. The AtN-derived cells have been reported to manifest certain neuronal functions in vivo. However, this approach has raised many new questions and alternative explanations regarding the biological features of the end products (e.g., iNs versus neuron-like cells, neural functional changes, etc.), developmental biology underpinnings, and neurobiological essentials. For this paper per se, we proposed to draw an unconventional distinction between direct cell conversion and direct cell reprogramming, relative to somatic nuclear transfer, based on the experimental methods utilized to initiate the transformation process, aiming to promote a more in-depth mechanistic exploration. Moreover, we have summarized the current tactics employed for AtN induction, comparisons between the bench endeavors concerning outcome tangibility, and discussion of the issues of published AtN protocols. Lastly, the urgency to clearly define/devise the theoretical frameworks, cell biological bases, and bench specifics to experimentally validate primary data of AtN studies was highlighted. Full article
(This article belongs to the Special Issue Neural Stem Cells: Developmental Mechanisms and Disease Modelling)
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25 pages, 1523 KiB  
Review
Boosting Neurogenesis in the Adult Hippocampus Using Antidepressants and Mesenchymal Stem Cells
by Marta Kot, Pawan Kumar Neglur, Anna Pietraszewska and Leonora Buzanska
Cells 2022, 11(20), 3234; https://doi.org/10.3390/cells11203234 - 14 Oct 2022
Cited by 9 | Viewed by 5582
Abstract
The hippocampus is one of the few privileged regions (neural stem cell niche) of the brain, where neural stem cells differentiate into new neurons throughout adulthood. However, dysregulation of hippocampal neurogenesis with aging, injury, depression and neurodegenerative disease leads to debilitating cognitive impacts. [...] Read more.
The hippocampus is one of the few privileged regions (neural stem cell niche) of the brain, where neural stem cells differentiate into new neurons throughout adulthood. However, dysregulation of hippocampal neurogenesis with aging, injury, depression and neurodegenerative disease leads to debilitating cognitive impacts. These debilitating symptoms deteriorate the quality of life in the afflicted individuals. Impaired hippocampal neurogenesis is especially difficult to rescue with increasing age and neurodegeneration. However, the potential to boost endogenous Wnt signaling by influencing pathway modulators such as receptors, agonists, and antagonists through drug and cell therapy-based interventions offers hope. Restoration and augmentation of hampered Wnt signaling to facilitate increased hippocampal neurogenesis would serve as an endogenous repair mechanism and contribute to hippocampal structural and functional plasticity. This review focuses on the possible interaction between neurogenesis and Wnt signaling under the control of antidepressants and mesenchymal stem cells (MSCs) to overcome debilitating symptoms caused by age, diseases, or environmental factors such as stress. It will also address some current limitations hindering the direct extrapolation of research from animal models to human application, and the technical challenges associated with the MSCs and their cellular products as potential therapeutic solutions. Full article
(This article belongs to the Special Issue Neural Stem Cells: Developmental Mechanisms and Disease Modelling)
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Graphical abstract

15 pages, 1224 KiB  
Review
Concise Review: Stem Cell Models of SCN1A-Related Encephalopathies—Current Perspective and Future Therapies
by Valery Zayat, Roza Szlendak and Dorota Hoffman-Zacharska
Cells 2022, 11(19), 3119; https://doi.org/10.3390/cells11193119 - 4 Oct 2022
Cited by 3 | Viewed by 2941
Abstract
Mutations in the SCN1A gene can cause a variety of phenotypes, ranging from mild forms, such as febrile seizures and generalized epilepsy with febrile seizures plus, to severe, such as Dravet and non-Dravet developmental epileptic encephalopathies. Until now, more than two thousand pathogenic [...] Read more.
Mutations in the SCN1A gene can cause a variety of phenotypes, ranging from mild forms, such as febrile seizures and generalized epilepsy with febrile seizures plus, to severe, such as Dravet and non-Dravet developmental epileptic encephalopathies. Until now, more than two thousand pathogenic variants of the SCN1A gene have been identified and different pathogenic mechanisms (loss vs. gain of function) described, but the precise molecular mechanisms responsible for the deficits exhibited by patients are not fully elucidated. Additionally, the phenotypic variability proves the involvement of other genetic factors in its final expression. This is the reason why animal models and cell line models used to explore the molecular pathology of SCN1A-related disorders are only of limited use. The results of studies based on such models cannot be directly translated to affected individuals because they do not address each patient’s unique genetic background. The generation of functional neurons and glia for patient-derived iPSCs, together with the generation of isogenic controls using CRISPR/Cas technology, and finally, the 3D brain organoid models, seem to be a good way to solve this problem. Here, we review SCN1A-related encephalopathies, as well as the stem cell models used to explore their molecular basis. Full article
(This article belongs to the Special Issue Neural Stem Cells: Developmental Mechanisms and Disease Modelling)
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26 pages, 5744 KiB  
Review
Cerebral Organoids as an Experimental Platform for Human Neurogenomics
by Tomasz J. Nowakowski and Sofie R. Salama
Cells 2022, 11(18), 2803; https://doi.org/10.3390/cells11182803 - 8 Sep 2022
Cited by 12 | Viewed by 6797
Abstract
The cerebral cortex forms early in development according to a series of heritable neurodevelopmental instructions. Despite deep evolutionary conservation of the cerebral cortex and its foundational six-layered architecture, significant variations in cortical size and folding can be found across mammals, including a disproportionate [...] Read more.
The cerebral cortex forms early in development according to a series of heritable neurodevelopmental instructions. Despite deep evolutionary conservation of the cerebral cortex and its foundational six-layered architecture, significant variations in cortical size and folding can be found across mammals, including a disproportionate expansion of the prefrontal cortex in humans. Yet our mechanistic understanding of neurodevelopmental processes is derived overwhelmingly from rodent models, which fail to capture many human-enriched features of cortical development. With the advent of pluripotent stem cells and technologies for differentiating three-dimensional cultures of neural tissue in vitro, cerebral organoids have emerged as an experimental platform that recapitulates several hallmarks of human brain development. In this review, we discuss the merits and limitations of cerebral organoids as experimental models of the developing human brain. We highlight innovations in technology development that seek to increase its fidelity to brain development in vivo and discuss recent efforts to use cerebral organoids to study regeneration and brain evolution as well as to develop neurological and neuropsychiatric disease models. Full article
(This article belongs to the Special Issue Neural Stem Cells: Developmental Mechanisms and Disease Modelling)
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22 pages, 1552 KiB  
Review
Interaction of Neural Stem Cells (NSCs) and Mesenchymal Stem Cells (MSCs) as a Promising Approach in Brain Study and Nerve Regeneration
by Agnieszka Kaminska, Klaudia Radoszkiewicz, Paulina Rybkowska, Aleksandra Wedzinska and Anna Sarnowska
Cells 2022, 11(9), 1464; https://doi.org/10.3390/cells11091464 - 26 Apr 2022
Cited by 30 | Viewed by 6590
Abstract
Rapid developments in stem cell research in recent years have provided a solid foundation for their use in medicine. Over the last few years, hundreds of clinical trials have been initiated in a wide panel of indications. Disorders and injuries of the nervous [...] Read more.
Rapid developments in stem cell research in recent years have provided a solid foundation for their use in medicine. Over the last few years, hundreds of clinical trials have been initiated in a wide panel of indications. Disorders and injuries of the nervous system still remain a challenge for the regenerative medicine. Neural stem cells (NSCs) are the optimal cells for the central nervous system restoration as they can differentiate into mature cells and, most importantly, functional neurons and glial cells. However, their application is limited by multiple factors such as difficult access to source material, limited cells number, problematic, long and expensive cultivation in vitro, and ethical considerations. On the other hand, according to the available clinical databases, most of the registered clinical trials involving cell therapies were carried out with the use of mesenchymal stem/stromal/signalling cells (MSCs) obtained from afterbirth or adult human somatic tissues. MSCs are the multipotent cells which can also differentiate into neuron-like and glia-like cells under proper conditions in vitro; however, their main therapeutic effect is more associated with secretory and supportive properties. MSCs, as a natural component of cell niche, affect the environment through immunomodulation as well as through the secretion of the trophic factors. In this review, we discuss various therapeutic strategies and activated mechanisms related to bilateral MSC–NSC interactions, differentiation of MSCs towards the neural cells (subpopulation of crest-derived cells) under the environmental conditions, bioscaffolds, or co-culture with NSCs by recreating the conditions of the neural cell niche. Full article
(This article belongs to the Special Issue Neural Stem Cells: Developmental Mechanisms and Disease Modelling)
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16 pages, 1120 KiB  
Review
Covering the Role of PGC-1α in the Nervous System
by Zuzanna Kuczynska, Erkan Metin, Michal Liput and Leonora Buzanska
Cells 2022, 11(1), 111; https://doi.org/10.3390/cells11010111 - 30 Dec 2021
Cited by 18 | Viewed by 4141
Abstract
The peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) is a well-known transcriptional coactivator involved in mitochondrial biogenesis. PGC-1α is implicated in the pathophysiology of many neurodegenerative disorders; therefore, a deep understanding of its functioning in the nervous system may lead to the development of new [...] Read more.
The peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) is a well-known transcriptional coactivator involved in mitochondrial biogenesis. PGC-1α is implicated in the pathophysiology of many neurodegenerative disorders; therefore, a deep understanding of its functioning in the nervous system may lead to the development of new therapeutic strategies. The central nervous system (CNS)-specific isoforms of PGC-1α have been recently identified, and many functions of PGC-1α are assigned to the particular cell types of the central nervous system. In the mice CNS, deficiency of PGC-1α disturbed viability and functioning of interneurons and dopaminergic neurons, followed by alterations in inhibitory signaling and behavioral dysfunction. Furthermore, in the ALS rodent model, PGC-1α protects upper motoneurons from neurodegeneration. PGC-1α is engaged in the generation of neuromuscular junctions by lower motoneurons, protection of photoreceptors, and reduction in oxidative stress in sensory neurons. Furthermore, in the glial cells, PGC-1α is essential for the maturation and proliferation of astrocytes, myelination by oligodendrocytes, and mitophagy and autophagy of microglia. PGC-1α is also necessary for synaptogenesis in the developing brain and the generation and maintenance of synapses in postnatal life. This review provides an outlook of recent studies on the role of PGC-1α in various cells in the central nervous system. Full article
(This article belongs to the Special Issue Neural Stem Cells: Developmental Mechanisms and Disease Modelling)
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