scholarly journals Model Systems of Motor Neuron Diseases As a Platform for Studying Pathogenic Mechanisms and Searching for Therapeutic Agents

Acta Naturae ◽  
2015 ◽  
Vol 7 (1) ◽  
pp. 19-36 ◽  
Author(s):  
K. R. Valetdinova ◽  
S. P. Medvedev ◽  
S. M. Zakian
Keyword(s):  
Stem Cells ◽  
Motor Neuron ◽  
Muscular Atrophy ◽  
Molecular Genetic ◽  
Embryonic Stem ◽  
Deep Understanding ◽  
Therapeutic Agents ◽  
Model Systems ◽  
Hereditary Diseases ◽  
Motor Neuron Diseases

Over the past 30 years, many molecular genetic mechanisms underlying motor neuron diseases (MNDs) have been discovered and studied. Among these diseases, amyotrophic lateral sclerosis (ALS), which causes the progressive degeneration and death of central and peripheral motor neurons, and spinal muscular atrophy (SMA), which is one of the inherited diseases that prevail among hereditary diseases in the pattern of child mortality, hold a special place. These diseases, like most nerve, neurodegenerative, and psychiatric diseases, cannot be treated appropriately at present. Artificial model systems, especially those that are based on the use of embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), are of paramount importance in searching for adequate therapeutic agents, as well as for a deep understanding of the MND pathogenesis. This review is mainly focused on the recent advance in the development of and research into cell and animal models of ALS and SMA. The main issues concerning the use of cellular technologies in biomedical applications are also described.

scholarly journals Motor Neuron Diseases in Sub-Saharan Africa: The Need for More Population-Based Studies

2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
Author(s):  
Emmanuel Quansah ◽  
Thomas K. Karikari
Keyword(s):  
Motor Neuron ◽  
Muscular Atrophy ◽  
Clinical Care ◽  
Treatment Options ◽  
Molecular Genetic ◽  
Population Based ◽  
Sub Saharan Africa ◽  
Motor Neuron Diseases ◽  
African Populations ◽  
Sub Saharan

Motor neuron diseases (MNDs) are devastating neurological diseases that are characterised by gradual degeneration and death of motor neurons. Major types of MNDs include amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). These diseases are incurable, with limited disease-modifying treatment options. In order to improve MND-based biomedical research, drug development, and clinical care, population-based studies will be important. These studies, especially among less-studied populations, might identify novel factors controlling disease susceptibility and resistance. To evaluate progress in MND research in Africa, we examined the published literature on MNDs in Sub-Saharan Africa to identify disease prevalence, genetic factors, and other risk factors. Our findings indicate that the amount of research evidence on MNDs in Sub-Saharan Africa is scanty; molecular and genetics-based studies are particularly lacking. While only a few genetic studies were identified, these studies strongly suggest that there appear to be population-specific causes of MNDs among Africans. MND genetic underpinnings vary among different African populations and also between African and non-African populations. Further studies, especially molecular, genetic and genomic studies, will be required to advance our understanding of MND biology among African populations. Insights from these studies would help to improve the timeliness and accuracy of clinical diagnosis and treatment.

Motor Neuron Diseases

2014 ◽  
Author(s):  
Elena Ratti ◽  
Merit E. Cudkowicz ◽  
James D Berry
Keyword(s):  
Motor Neuron ◽  
Motor Neurons ◽  
Viral Infections ◽  
Inflammatory Responses ◽  
Muscular Atrophy ◽  
Experimental Therapy ◽  
Rapid Progression ◽  
Motor Neuron Diseases ◽  
Efficacy Outcome ◽  
Single Disease Entity

The motor neuron diseases (MNDs) are a family of diseases commonly categorized by their propensity to affect upper or lower motor neurons and by their mode of inheritance. The chapter provides some content on infectious MNDs caused by viral infections affecting the motor neurons in the anterior horn of the spinal cord. However, the chapter devotes most of its attention to the inherited and sporadically occurring MNDs. The majority of research into adult MND focuses on amyotrophic lateral sclerosis (ALS) due to its high prevalence, rapid progression, and phenotypical similarities between its inherited form and its sporadic form. As our knowledge of genetic mechanisms underlying ALS pathology has grown, common themes have emerged. These include abnormalities in RNA biology, axonal transport, protein folding, and inflammatory responses. These themes currently drive much of the direction in ALS experimental therapy development. It is clear that MND is complex and involves several different molecular pathways. Given this complexity, ALS might not be a single disease entity, and if this is the case, treatment approaches may need to be targeted to specific pathologies rather than all ALS patients on a broad scale. Chapter content is enhanced by tables outlining the types of MNDs, criteria for supporting a diagnosis, first-line workup, the genes associated with ALS, ALS efficacy outcome measures, symptom management of ALS, and spinal muscular atrophy classification. Mechanisms of ALS are illustrated, and clinical photographs demonstrate symptoms. This chapter contains 252 references. 

Investigation of the Stem Cells Used in Modeling Human Placental Trophoblast

2021 ◽  
Author(s):  
Lulu Ji ◽  
Lin Wang
Keyword(s):  
Stem Cells ◽  
Molecular Mechanisms ◽  
Embryonic Stem ◽  
Cell Lineage ◽  
Cell Types ◽  
Model Systems ◽  
Alternative Methods ◽  
Laboratory Animals ◽  
Placental Development ◽  
Induced Pluripotent

Human placenta is vital for fetal development, and act as an interface between the fetus and the expecting mother. Abnormal placentati on underpins various pregnancy complications such as miscarriage, pre-eclampsia and intrauterine growth restriction. Despite the important role of placenta, the molecular mechanisms governing placental formation and trophoblast cell lineage specification is poorly understand. It is mostly due to the lack of appropriate model system. The great various in placental types across mammals make it limit for the use of laboratory animals in studying human placental development. However, over the past few years, alternative methods have been employed, including human embryonic stem cells, induced pluripotent stem cells, human trophoblast stem cell, and 3-dimensional organoids. Herein, we summarize the present knowledge about human development, differentiated cell types in the trophoblast epithelium and current human placental trophoblast model systems.

scholarly journals Pancreatic Progenitors and Organoids as a Prerequisite to Model Pancreatic Diseases and Cancer

2019 ◽  
Vol 2019 ◽  
pp. 1-11 ◽  
Author(s):  
Meike Hohwieler ◽  
Martin Müller ◽  
Pierre-Olivier Frappart ◽  
Sandra Heller
Keyword(s):  
Stem Cells ◽  
Pluripotent Stem Cells ◽  
Disease Modeling ◽  
Embryonic Stem ◽  
Cell Types ◽  
Genetically Engineered ◽  
Hereditary Diseases ◽  
Pancreatic Diseases ◽  
Pancreatic Progenitors

Embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) are characterized by their unique capacity to stepwise differentiate towards any particular cell type in an adult organism. Pluripotent stem cells provide a beneficial platform to model hereditary diseases and even cancer development. While the incidence of pancreatic diseases such as diabetes and pancreatitis is increasing, the understanding of the underlying pathogenesis of particular diseases remains limited. Only a few recent publications have contributed to the characterization of human pancreatic development in the fetal stage. Hence, most knowledge of pancreatic specification is based on murine embryology. Optimizing and understanding current in vitro protocols for pancreatic differentiation of ESCs and iPSCs constitutes a prerequisite to generate functional pancreatic cells for better disease modeling and drug discovery. Moreover, human pancreatic organoids derived from pluripotent stem cells, organ-restricted stem cells, and tumor samples provide a powerful technology to model carcinogenesis and hereditary diseases independent of genetically engineered mouse models. Herein, we summarize recent advances in directed differentiation of pancreatic organoids comprising endocrine cell types. Beyond that, we illustrate up-and-coming applications for organoid-based platforms.

scholarly journals Survival Motor Neuron Protein Participates in Mouse Germ Cell Development and Spermatogonium Maintenance

2020 ◽  
Vol 21 (3) ◽  
pp. 794 ◽  
Author(s):  
Wei-Fang Chang ◽  
Jie Xu ◽  
Tzu-Ying Lin ◽  
Jing Hsu ◽  
Hsiu-Mei Hsieh-Li ◽  
...  
Keyword(s):  
Stem Cells ◽  
Germ Cell ◽  
Motor Neuron ◽  
Cell Biology ◽  
Critical Role ◽  
Embryonic Stem ◽  
Cell Development ◽  
Survival Motor Neuron ◽  
Specific Marker ◽  
Germ Cell Development

The defective human survival motor neuron 1 (SMN1) gene leads to spinal muscular atrophy (SMA), the most common genetic cause of infant mortality. We previously reported that loss of SMN results in rapid differentiation of Drosophila germline stem cells and mouse embryonic stem cells (ESCs), indicating that SMN also plays important roles in germ cell development and stem cell biology. Here, we show that in healthy mice, SMN is highly expressed in the gonadal tissues, prepubertal spermatogonia, and adult spermatocytes, whereas low SMN expression is found in differentiated spermatid and sperm. In SMA-like mice, the growth of testis tissues is retarded, accompanied with gamete development abnormalities and loss of the spermatogonia-specific marker. Consistently, knockdown of Smn1 in spermatogonial stem cells (SSCs) leads to a compromised regeneration capacity in vitro and in vivo in transplantation experiments. In SMA-like mice, apoptosis and accumulation of the R-loop structure were significantly elevated, indicating that SMN plays a critical role in the survival of male germ cells. The present work demonstrates that SMN, in addition to its critical roles in neuronal development, participates in mouse germ cell and spermatogonium maintenance.

scholarly journals Human embryonic stem cell-derived organoid retinoblastoma reveals a cancerous origin

2020 ◽  
Vol 117 (52) ◽  
pp. 33628-33638
Author(s):  
Hui Liu ◽  
Yan Zhang ◽  
You-You Zhang ◽  
Yan-Ping Li ◽  
Zi-Qi Hua ◽  
...  
Keyword(s):  
Stem Cells ◽  
Human Embryonic Stem Cell ◽  
Embryonic Stem ◽  
Therapeutic Agents ◽  
Genetically Engineered ◽  
Akt Pathway ◽  
Sequencing Analysis ◽  
Cell Of Origin ◽  
Single Cell Sequencing ◽  
Genome Wide

Retinoblastoma (Rb) is the most prevalent intraocular malignancy in children, with a worldwide survival rate <30%. We have developed a cancerous model of Rb in retinal organoids derived from genetically engineered human embryonic stem cells (hESCs) with a biallelic mutagenesis of the RB1 gene. These organoid Rbs exhibit properties highly consistent with Rb tumorigenesis, transcriptome, and genome-wide methylation. Single-cell sequencing analysis suggests that Rb originated from ARR3-positive maturing cone precursors during development, which was further validated by immunostaining. Notably, we found that the PI3K-Akt pathway was aberrantly deregulated and its activator spleen tyrosine kinase (SYK) was significantly up-regulated. In addition, SYK inhibitors led to remarkable cell apoptosis in cancerous organoids. In conclusion, we have established an organoid Rb model derived from genetically engineered hESCs in a dish that has enabled us to trace the cell of origin and to test novel candidate therapeutic agents for human Rb, shedding light on the development and therapeutics of other malignancies.

scholarly journals Modeling Poliovirus Infection Using Human Engineered Neural Tissue Enriched With Motor Neuron Derived From Embryonic Stem Cells

2021 ◽  
Vol 8 ◽  
Author(s):  
Érika Cosset ◽  
Youssef Hibaoui ◽  
Sten Ilmjärv ◽  
Pierre-Yves Dietrich ◽  
Caroline Tapparel ◽  
...  
Keyword(s):  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Embryonic Stem ◽  
Neural Tissue ◽  
Enveloped Virus ◽  
Standardized Protocol ◽  
Molecular Events

Poliomyelitis is caused by poliovirus (PV), a positive strand non-enveloped virus. Since its discovery in the 1950s, several cell culture and molecular methods have been developed to detect and characterize the various strains of PV. Here, we provide an accurate and standardized protocol to differentiate human embryonic stem cells (hESCs) toward engineered neural tissue enriched with motor neurons (MN ENTs). These MN ENTs expressed markers of motor neuron CHAT and Hb-9 as revealed by immunofluorescence staining and quantitative RT-PCR. Interestingly, our results suggest that motor neurons are responsible for the permissiveness of poliovirus within the MN ENTs. Moreover, our study revealed the molecular events occurring upon PV-3 infection in the MN ENTs and highlighted the modulation of a set of genes involved in EGR-EP300 complex. Collectively, we report the development of a reliable in vitro model to investigate the pathophysiology of PV infection, allowing to both design and assess novel therapeutic approaches against PV infection.

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